13-26337623-C-A

Position:

• chr13-26337623-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001260.3(CDK8):​c.185C>A​(p.Ser62Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000776 in 1,288,946 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: CDK8 NM_001260.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P: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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-26337623-C-A is Pathogenic according to our data. Variant chr13-26337623-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 631491.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK8	NM_001260.3	c.185C>A	p.Ser62Ter	stop_gained	2/13	ENST00000381527.8	NP_001251.1
CDK8	NM_001318368.2	c.185C>A	p.Ser62Ter	stop_gained	2/13		NP_001305297.1
CDK8	XM_047430033.1	c.5C>A	p.Ser2Ter	stop_gained	3/14		XP_047285989.1
CDK8	NM_001346501.2	c.-277C>A		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>A	p.Ser62Ter	stop_gained	2/13	1	NM_001260.3	ENSP00000370938	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.76e-7 AC: 1 AN: 1288946 Hom.: 0 Cov.: 24 AF XY: 0.00000157 AC XY: 1 AN XY: 637216

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: 0.0000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ebstein anomaly;C0235833:Congenital diaphragmatic hernia;C0392482:Common atrium;C0424503:Abnormal facial shape;C0595939:Stillbirth;C3278923:Ventriculomegaly;CN130023:Heart, malformation of Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Diagnostics Division, CENTRE FOR DNA FINGERPRINTING AND DIAGNOSTICS

May 16, 2019

c.185C>T (p.Ser62Leu) missense variant in CDK8 has been reported among five individuals with developmental disorder. De novo missense variants in CDK8 gene have been recently implicated in syndromic developmental disorder (PMID:30905399). The reported variant is a heterozygous stop gain variant (c.185C>A:p.Ser62*) at the same position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	49
DANN	Uncertain	0.99
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A
Vest4		0.90
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.38		Position offset: 19

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;