13-26337623-C-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001260.3(CDK8):c.185C>T(p.Ser62Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,288,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S62W) has been classified as Likely pathogenic.
Frequency
Consequence
NM_001260.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CDK8 | NM_001260.3 | c.185C>T | p.Ser62Leu | missense_variant | 2/13 | ENST00000381527.8 | |
CDK8 | NM_001318368.2 | c.185C>T | p.Ser62Leu | missense_variant | 2/13 | ||
CDK8 | XM_047430033.1 | c.5C>T | p.Ser2Leu | missense_variant | 3/14 | ||
CDK8 | NM_001346501.2 | c.-277C>T | 5_prime_UTR_variant | 2/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CDK8 | ENST00000381527.8 | c.185C>T | p.Ser62Leu | missense_variant | 2/13 | 1 | NM_001260.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000310 AC: 4AN: 1288948Hom.: 0 Cov.: 24 AF XY: 0.00000157 AC XY: 1AN XY: 637218
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Intellectual developmental disorder with hypotonia and behavioral abnormalities Pathogenic:3Other:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 11, 2023 | - - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpreted as Pathogenic and reported on 03-18-2021 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Pathogenic, no assertion criteria provided | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jul 29, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München | Mar 26, 2020 | - - |
Complex neurodevelopmental disorder with or without congenital anomalies Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Molecular Genetics, Royal Melbourne Hospital | Jun 06, 2023 | This sequence change in CDK8 is predicted to replace serine with leucine at codon 62, p.(Ser62Leu). The serine residue is highly conserved (97/97 vertebrates, UCSC), and is located in the protein kinase domain. There is a large physicochemical difference between serine and leucine. CDK8, in which the variant was identified, is a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (gnomAD v2.1 missense constraint). This variant is absent from the population database gnomAD v2.1 and v3.1. This variant has been identified as a de novo occurrence with confirmed parental relationships in four individuals, as a de novo occurrence with unconfirmed parental relationships in five individuals, and expected de novo with unknown inheritance in two individuals, all with a syndromic neurodevelopmental disorder (PMID: 30905399, 33958710; DECIPHER patient: 293709, 409614; ClinVar: SCV001430065.1, SCV001439334.1, SCV002075047.1). Phosphorylation assays in a mammalian cell line showed reduced STAT1 phosphorylation indicating that this variant impacts protein function (PMID: 30905399). Computational evidence predicts a deleterious effect for the missense substitution (REVEL = 0.644). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as PATHOGENIC. Following criteria are met: PS2/PM6_VeryStrong, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP2, PP3. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at