Variant: NM_001323289.2(CDKL5):c.1612A>G (p.Thr538Ala)

Version: 1.0
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CA412361958

3343996 (ClinVar)

Gene: CDKL5 (HGNC:6792)

Condition: CDKL5 disorder

Inheritance Mode: X-linked inheritance

UUID: ba323547-c9a0-4c76-ba58-36ec24d41002

Approved on: 2025-06-25

Published on: 2025-08-01

HGVS expressions

NM_001323289.2:c.1612A>G
NM_001323289.2(CDKL5):c.1612A>G (p.Thr538Ala)
NC_000023.11:g.18604536A>G
CM000685.2:g.18604536A>G
NC_000023.10:g.18622656A>G
CM000685.1:g.18622656A>G
NC_000023.9:g.18532577A>G
NG_008475.1:g.183932A>G
ENST00000623535.2:c.1612A>G
ENST00000635828.1:c.1612A>G
ENST00000674046.1:c.1612A>G
ENST00000379989.6:c.1612A>G
ENST00000379996.7:c.1612A>G
ENST00000463994.4:c.1612A>G
ENST00000623535.1:c.1612A>G
NM_001037343.1:c.1612A>G
NM_003159.2:c.1612A>G
NM_001323289.1:c.1612A>G
NM_001037343.2:c.1612A>G
NM_003159.3:c.1612A>G

Likely Benign

• Met criteria codes: BS2_Supporting BP4

• Not Met criteria codes: PS4 PP4 PM2 BS1

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CDKL5 Version 4.1.0

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The highest population minor allele frequency of the p.Thr538Ala variant in CDKL5 in gnomAD v4.1 is 0.000004468 in the Non-Finnish European population (not sufficient to meet BS1 criteria). The p.Thr538Ala variant is observed in at least 1 unaffected individual (Internal database - Ambry Genetics) (BS2_Supporting). The computational predictor REVEL gives a score of 0.214, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4). In summary, the p.Thr538Ala variant in CDKL5 is classified as likely benign based on the ACMG/AMP criteria (BS2_Supporting, BP4). (CDKL5 Specifications v.4.1; curation approved on 06/25/2025)

Met criteria codes

• BS2_Supporting: The p.Thr538Ala variant is observed in at least 1 unaffected individual (Internal database - Ambry Genetics).
• BP4: The computational predictor REVEL gives a score of 0.214, which is below the threshold of 0.290, evidence that does not predict a damaging effect on CDKL5 function (BP4).

Not Met criteria codes

• PS4: PM2 not met.
• PP4: Computational prediction analysis tools are inconclusive for this variant.
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS1: The highest population minor allele frequency of the p.Thr538Ala variant in CDKL5 in gnomAD v4.1 is 0.000004468 in Non-Finnish European population (not sufficient to meet BS1 criteria).