6-110621297-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_015076.5(CDK19):c.1184C>T(p.Ala395Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000938 in 1,608,992 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000089 (1 hom.)
• Consequence: CDK19 NM_015076.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.98

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005859375).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDK19	NM_015076.5	c.1184C>T	p.Ala395Val	missense_variant	12/13	ENST00000368911.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDK19	ENST00000368911.8	c.1184C>T	p.Ala395Val	missense_variant	12/13	1	NM_015076.5	P1
CDK19	ENST00000323817.7	c.1004C>T	p.Ala335Val	missense_variant	13/14	1
CDK19	ENST00000413605.6	c.872C>T	p.Ala291Val	missense_variant	11/12	1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000255 AC: 62 AN: 243564 Hom.: 0 AF XY: 0.000190 AC XY: 25 AN XY: 131886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00296

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.0000886 AC: 129 AN: 1456652 Hom.: 1 Cov.: 31 AF XY: 0.0000843 AC XY: 61 AN XY: 724008

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00240

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000541

Gnomad4 OTH exome AF: 0.000366

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000146 Hom.: 1

Bravo AF: 0.000208

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Microcephaly Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Pediatrics, Samsung Medical Center, Samsung Medical Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	18
Dann	Benign	0.97
DEOGEN2	Benign	0.013	T;T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0059	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.94	N;N;N
PrimateAI	Benign	0.46	T
REVEL	Benign	0.030
Sift4G	Benign	0.57	T;T;T
Polyphen		0.22	.;B;.
Vest4		0.16
MVP		0.35
MPC		0.46
ClinPred		0.038	T
GERP RS		5.1
Varity_R		0.030
gMVP		0.20

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: rs55914301; hg19: chr6-110942500; COSMIC: COSV60454390; COSMIC: COSV60454390;