chr13-26337623-C-A

Variant names:

• chr13-26337623-C-A
• rs1565977796
• NM_001260.3:c.185C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_001260.3(CDK8):​c.185C>A​(p.Ser62*) 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
• Publications: 0 publications found

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]

CDK8 Gene-Disease associations (from GenCC):

• intellectual developmental disorder with hypotonia and behavioral abnormalities

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 VariationId is 631491.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001260.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK8	NM_001260.3	MANE Select	c.185C>A	p.Ser62*	stop_gained	Exon 2 of 13	NP_001251.1	P49336-1
	CDK8	NM_001318368.2		c.185C>A	p.Ser62*	stop_gained	Exon 2 of 13	NP_001305297.1	P49336-2
	CDK8	NM_001346501.2		c.-277C>A		5_prime_UTR	Exon 2 of 12	NP_001333430.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK8	ENST00000381527.8	TSL:1 MANE Select	c.185C>A	p.Ser62*	stop_gained	Exon 2 of 13	ENSP00000370938.3	P49336-1
	CDK8	ENST00000536792.5	TSL:1	n.185C>A		non_coding_transcript_exon	Exon 2 of 12	ENSP00000437696.1	F5H6D4
	CDK8	ENST00000923333.1		c.185C>A	p.Ser62*	stop_gained	Exon 2 of 14	ENSP00000593392.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27222

American (AMR) AF: 0.00 AC: 0 AN: 23728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20926

East Asian (EAS) AF: 0.00 AC: 0 AN: 34086

South Asian (SAS) AF: 0.0000190 AC: 1 AN: 52648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5096

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1025710

Other (OTH) AF: 0.00 AC: 0 AN: 52242

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ebstein anomaly;C0018798:Heart, malformation of;C0235833:Congenital diaphragmatic hernia;C0392482:Common atrium;C0424503:Abnormal facial shape;C0595939:Stillbirth;C3278923:Ventriculomegaly (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.5
Vest4		0.90
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1565977796; hg19: chr13-26911760;