chr13-26337623-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001346501.2(CDK8):​c.-277C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,288,948 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: CDK8 NM_001346501.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O: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: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93
• PP5: Variant 13-26337623-C-T is Pathogenic according to our data. 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346501.2. 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>T	p.Ser62Leu	missense	Exon 2 of 13	NP_001251.1	P49336-1
	CDK8	NM_001346501.2		c.-277C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 12	NP_001333430.1
	CDK8	NM_001318368.2		c.185C>T	p.Ser62Leu	missense	Exon 2 of 13	NP_001305297.1	P49336-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK8	ENST00000381527.8	TSL:1 MANE Select	c.185C>T	p.Ser62Leu	missense	Exon 2 of 13	ENSP00000370938.3	P49336-1
	CDK8	ENST00000536792.5	TSL:1	n.185C>T		non_coding_transcript_exon	Exon 2 of 12	ENSP00000437696.1	F5H6D4
	CDK8	ENST00000923333.1		c.185C>T	p.Ser62Leu	missense	Exon 2 of 14	ENSP00000593392.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000310 AC: 4 AN: 1288948 Hom.: 0 Cov.: 24 AF XY: 0.00000157 AC XY: 1 AN XY: 637218

⚠️ 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: 0.00 AC: 0 AN: 52650

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: 0.00000390 AC: 4 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 = 0.0126737), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Intellectual developmental disorder with hypotonia and behavioral abnormalities (5)
1	-	-	Complex neurodevelopmental disorder with or without congenital anomalies (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.48	T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.64
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.85		Loss of disorder (P = 0.0755)
MVP		0.87
MPC		2.3
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.92
gMVP		0.89
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;