chr13-26254670-G-A

Position:

• chr13-26254670-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001260.3(CDK8):​c.29G>A​(p.Ser10Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDK8 NM_001260.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.15

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17349586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK8	NM_001260.3	c.29G>A	p.Ser10Asn	missense_variant	1/13	ENST00000381527.8
CDK8	NM_001318368.2	c.29G>A	p.Ser10Asn	missense_variant	1/13
CDK8	NM_001346501.2	c.-433G>A		5_prime_UTR_variant	1/12
CDK8	XM_047430033.1	c.-202G>A		5_prime_UTR_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK8	ENST00000381527.8	c.29G>A	p.Ser10Asn	missense_variant	1/13	1	NM_001260.3	P1
CDK8	ENST00000536792.5	c.29G>A	p.Ser10Asn	missense_variant, NMD_transcript_variant	1/12	1
CDK8	ENST00000700501.1	c.29G>A	p.Ser10Asn	missense_variant, NMD_transcript_variant	1/12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.29G>A (p.S10N) alteration is located in exon 1 (coding exon 1) of the CDK8 gene. This alteration results from a G to A substitution at nucleotide position 29, causing the serine (S) at amino acid position 10 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.96	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.072
Sift	Benign	0.39	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.31		Loss of phosphorylation at S10 (P = 0.0107);
MVP		0.44
MPC		1.2
ClinPred		0.80	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-26828807; COSMIC: COSV105325818;