6-110623334-T-C

Variant names:

• chr6-110623334-T-C
• rs777727767
• NM_015076.5:c.889A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_015076.5(CDK19):​c.889A>G​(p.Met297Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 6.8e-7 (0 hom.)
• Consequence: CDK19 NM_015076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63
• Publications: 0 publications found

Genes affected

CDK19 (HGNC:19338): (cyclin dependent kinase 19) This gene encodes a protein that is one of the components of the Mediator co-activator complex. The Mediator complex is a multi-protein complex required for transcriptional activation by DNA binding transcription factors of genes transcribed by RNA polymerase II. The protein encoded by this gene is similar to cyclin-dependent kinase 8 which can also be a component of the Mediator complex. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2014]

CDK19 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 87

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• undetermined early-onset epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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 7 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.5632 (above the threshold of 3.09). Trascript score misZ: 2.7618 (below the threshold of 3.09). GenCC associations: The gene is linked to developmental and epileptic encephalopathy, 87, undetermined early-onset epileptic encephalopathy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.407774).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK19	NM_015076.5	c.889A>G	p.Met297Val	missense_variant	Exon 9 of 13	ENST00000368911.8	NP_055891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK19	ENST00000368911.8	c.889A>G	p.Met297Val	missense_variant	Exon 9 of 13	1	NM_015076.5	ENSP00000357907.3
CDK19	ENST00000323817.7	c.709A>G	p.Met237Val	missense_variant	Exon 10 of 14	1		ENSP00000317665.3
CDK19	ENST00000413605.6	c.577A>G	p.Met193Val	missense_variant	Exon 8 of 12	1		ENSP00000410604.3
CDK19	ENST00000457688.5	c.709A>G	p.Met237Val	missense_variant	Exon 10 of 10	5		ENSP00000415621.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461702 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727136

⚠️ 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: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111876

Other (OTH) AF: 0.00 AC: 0 AN: 60392

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 297 of the CDK19 protein (p.Met297Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDK19-related conditions. ClinVar contains an entry for this variant (Variation ID: 1393897). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T;T;.;T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.47	.;N;.;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-2.0	.;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.38	.;T;T;T
Sift4G	Benign	0.28	T;T;T;T
Polyphen		0.94	.;P;.;.
Vest4		0.63
MutPred		0.44		.;Loss of MoRF binding (P = 0.106);.;.;
MVP		0.41
MPC		2.4
ClinPred		0.92	D
GERP RS		5.9
Varity_R		0.15
gMVP		0.75
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs777727767; hg19: chr6-110944537;