6-110632087-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_015076.5(CDK19):c.589T>C(p.Phe197Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CDK19 NM_015076.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.95

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-110632087-A-G is Pathogenic according to our data. Variant chr6-110632087-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 975817.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK19	NM_015076.5	c.589T>C	p.Phe197Leu	missense_variant	6/13	ENST00000368911.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK19	ENST00000368911.8	c.589T>C	p.Phe197Leu	missense_variant	6/13	1	NM_015076.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 87 Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Zarate Arkansas Children's Genetics Clinic, Arkansas Children's Hospital

Aug 11, 2020

De novo variant, in conserved residue, absent in population databases, located in functional domain with other variants -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.020
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.59	D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-1.3	N;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.8	D;D;D
REVEL	Uncertain	0.34
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.080	B;.;.
Vest4		0.78
MutPred		0.56		Loss of sheet (P = 0.1158);.;.;
MVP		0.66
MPC		1.7
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.36
gMVP		0.85

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

Publications

LitVar

Other links and lift over

dbSNP: rs1779473436; hg19: chr6-110953290;