13-26337623-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_001260.3(CDK8):​c.185C>G​(p.Ser62Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S62L) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK8 NM_001260.3 missense
• Clinical Significance: Likely 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-26337623-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 805981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 13-26337623-C-G is Pathogenic according to our data. Variant chr13-26337623-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3236205.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>G	p.Ser62Trp	missense	Exon 2 of 13	NP_001251.1	P49336-1
	CDK8	NM_001318368.2		c.185C>G	p.Ser62Trp	missense	Exon 2 of 13	NP_001305297.1	P49336-2
	CDK8	NM_001346501.2		c.-277C>G		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>G	p.Ser62Trp	missense	Exon 2 of 13	ENSP00000370938.3	P49336-1
	CDK8	ENST00000536792.5	TSL:1	n.185C>G		non_coding_transcript_exon	Exon 2 of 12	ENSP00000437696.1	F5H6D4
	CDK8	ENST00000923333.1		c.185C>G	p.Ser62Trp	missense	Exon 2 of 14	ENSP00000593392.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual developmental disorder with hypotonia and behavioral abnormalities (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.83		Loss of disorder (P = 0.0425)
MVP		0.82
MPC		2.9
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.95
gMVP		0.95
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1565977796; hg19: chr13-26911760;