13-26337623-C-T

Position:

• chr13-26337623-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CDK8 NM_001260.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.46

Genes affected

CDK8 (HGNC:1779): (cyclin dependent kinase 8) This gene encodes a member of the cyclin-dependent protein kinase (CDK) family. CDK family members are known to be important regulators of cell cycle progression. This kinase and its regulatory subunit, cyclin C, are components of the Mediator transcriptional regulatory complex, involved in both transcriptional activation and repression by phosphorylation of the carboxy-terminal domain of the largest subunit of RNA polymerase II. This kinase regulates transcription by targeting the cyclin-dependent kinase 7 subunits of the general transcription initiation factor IIH, thus providing a link between the Mediator complex and the basal transcription machinery. Multiple pseudogenes of this gene have been identified. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 13-26337623-C-T is Pathogenic according to our data. Variant chr13-26337623-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 805981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-26337623-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK8	NM_001260.3	c.185C>T	p.Ser62Leu	missense_variant	2/13	ENST00000381527.8	NP_001251.1
CDK8	NM_001318368.2	c.185C>T	p.Ser62Leu	missense_variant	2/13		NP_001305297.1
CDK8	XM_047430033.1	c.5C>T	p.Ser2Leu	missense_variant	3/14		XP_047285989.1
CDK8	NM_001346501.2	c.-277C>T		5_prime_UTR_variant	2/12		NP_001333430.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK8	ENST00000381527.8	c.185C>T	p.Ser62Leu	missense_variant	2/13	1	NM_001260.3	ENSP00000370938	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000310 AC: 4 AN: 1288948 Hom.: 0 Cov.: 24 AF XY: 0.00000157 AC XY: 1 AN XY: 637218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000390

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual developmental disorder with hypotonia and behavioral abnormalities Pathogenic:3 Other:1

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, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 26, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 11, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Jul 29, 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.85		Loss of disorder (P = 0.0755);
MVP		0.87
MPC		2.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.92
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1565977796; hg19: chr13-26911760; COSMIC: COSV67420297;