13-26254741-C-A

Variant names:

• chr13-26254741-C-A
• rs2137842744
• NM_001260.3:c.100C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001260.3(CDK8):​c.100C>A​(p.His34Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,124 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H34D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDK8 NM_001260.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.17
• 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 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001260.3
• 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.

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.100C>A	p.His34Asn	missense	Exon 1 of 13	NP_001251.1	P49336-1
	CDK8	NM_001318368.2		c.100C>A	p.His34Asn	missense	Exon 1 of 13	NP_001305297.1	P49336-2
	CDK8	NM_001346501.2		c.-362C>A		5_prime_UTR	Exon 1 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.100C>A	p.His34Asn	missense	Exon 1 of 13	ENSP00000370938.3	P49336-1
	CDK8	ENST00000536792.5	TSL:1	n.100C>A		non_coding_transcript_exon	Exon 1 of 12	ENSP00000437696.1	F5H6D4
	CDK8	ENST00000923333.1		c.100C>A	p.His34Asn	missense	Exon 1 of 14	ENSP00000593392.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460124 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726272

⚠️ 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: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25846

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85740

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111308

Other (OTH) AF: 0.00 AC: 0 AN: 60286

⚠️ 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.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Benign	0.0091	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	34
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.34	N
PhyloP100		7.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.38
Sift	Benign	0.14	T
Sift4G	Benign	0.28	T
Polyphen		0.95	P
Vest4		0.71
MutPred		0.54		Gain of MoRF binding (P = 0.1097)
MVP		0.51
MPC		2.0
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.69
gMVP		0.84
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.37		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: -3

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

Other links and lift over

dbSNP: rs2137842744; hg19: chr13-26828878;