Genetic Variant CDK8:p.Ile54Val (chr13-26337598-A-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001260.3(CDK8):c.160A>G(p.Ile54Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CDK8
NM_001260.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 8.81

Publications

0 publications found

Variant links:

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)

CDK8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: 3.6819 (above the threshold of 3.09). Trascript score misZ: 2.9117 (below the threshold of 3.09). GenCC associations: The gene is linked to intellectual developmental disorder with hypotonia and behavioral abnormalities.

BP4

Computational evidence support a benign effect (MetaRNN=0.40493912).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK8	NM_001260.3	MANE Select	c.160A>G	p.Ile54Val	missense	Exon 2 of 13	NP_001251.1	P49336-1
CDK8	NM_001318368.2		c.160A>G	p.Ile54Val	missense	Exon 2 of 13	NP_001305297.1	P49336-2
CDK8	NM_001346501.2		c.-302A>G		5_prime_UTR	Exon 2 of 12	NP_001333430.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CDK8	ENST00000381527.8	TSL:1 MANE Select	c.160A>G	p.Ile54Val	missense	Exon 2 of 13	ENSP00000370938.3	P49336-1
CDK8	ENST00000536792.5	TSL:1	n.160A>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000437696.1	F5H6D4
CDK8	ENST00000923333.1		c.160A>G	p.Ile54Val	missense	Exon 2 of 14	ENSP00000593392.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1311550

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

648972

African (AFR)

AF:

0.00

AC:

AN:

27812

American (AMR)

AF:

0.00

AC:

AN:

24876

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21398

East Asian (EAS)

AF:

0.00

AC:

AN:

34938

South Asian (SAS)

AF:

0.00

AC:

AN:

56308

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5194

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1039566

Other (OTH)

AF:

0.00

AC:

AN:

53304

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

CDK8-related disorder (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.025

MetaRNN

Benign

0.40

MetaSVM

Benign

-0.62

MutationAssessor

Benign

-0.12

PhyloP100

8.8

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.83

REVEL

Benign

0.28

Sift

Benign

0.097

Sift4G

Benign

0.18

Polyphen

0.89

Vest4

0.41

MutPred

0.66

Gain of ubiquitination at K52 (P = 0.1106)

MVP

0.59

MPC

1.5

ClinPred

0.95

GERP RS

5.6

Varity_R

0.48

gMVP

0.76

Mutation Taster

=50/50

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over