6-110614558-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015076.5(CDK19):c.1486T>A(p.Ser496Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK19 NM_015076.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13077256).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK19	NM_015076.5	c.1486T>A	p.Ser496Thr	missense_variant	13/13	ENST00000368911.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK19	ENST00000368911.8	c.1486T>A	p.Ser496Thr	missense_variant	13/13	1	NM_015076.5	P1
CDK19	ENST00000323817.7	c.1306T>A	p.Ser436Thr	missense_variant	14/14	1
CDK19	ENST00000413605.6	c.1174T>A	p.Ser392Thr	missense_variant	12/12	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Developmental and epileptic encephalopathy, 87 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

-

The missense c.1486T>A p.Ser496Thr variant in CDK19 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ser496Thr variant is novel not in any individuals in both gnomAD Exomes and 1000 Genomes databases. This variant has not been reported to the ClinVar database. The amino acid change p.Ser496Thr in CDK19 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ser at position 496 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Benign	0.94
DEOGEN2	Benign	0.014	T;T;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.035
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.74	T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.52	T
REVEL	Benign	0.10
Sift4G	Benign	0.087	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.15
MutPred		0.10		.;Loss of phosphorylation at S496 (P = 0.027);.;
MVP		0.37
MPC		0.42
ClinPred		0.40	T
GERP RS		3.3
Varity_R		0.15
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-110935761;