2-201835652-G-C

Variant names:

• chr2-201835652-G-C
• rs142416956
• NM_001366386.2:c.740G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001366386.2(CDK15):​c.740G>C​(p.Arg247Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000872 in 1,605,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CDK15 NM_001366386.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.83
• Publications: 0 publications found

Genes affected

CDK15 (HGNC:14434): (cyclin dependent kinase 15) Enables protein serine/threonine kinase activity. Predicted to be involved in protein phosphorylation and regulation of transcription involved in G1/S transition of mitotic cell cycle. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366386.2. 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
	CDK15	NM_001366386.2	MANE Select	c.740G>C	p.Arg247Pro	missense	Exon 8 of 14	NP_001353315.1	Q96Q40-1
	CDK15	NM_001261435.1		c.740G>C	p.Arg247Pro	missense	Exon 8 of 14	NP_001248364.1	Q96Q40-5
	CDK15	NM_001261436.1		c.740G>C	p.Arg247Pro	missense	Exon 8 of 13	NP_001248365.1	Q96Q40-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDK15	ENST00000652192.3	MANE Select	c.740G>C	p.Arg247Pro	missense	Exon 8 of 14	ENSP00000498608.2	Q96Q40-1
	CDK15	ENST00000450471.6	TSL:1	c.740G>C	p.Arg247Pro	missense	Exon 8 of 14	ENSP00000406472.2	Q96Q40-5
	CDK15	ENST00000434439.1	TSL:1	c.740G>C	p.Arg247Pro	missense	Exon 8 of 13	ENSP00000412775.1	Q96Q40-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151740 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000797 AC: 2 AN: 251010 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000825 AC: 12 AN: 1454064 Hom.: 0 Cov.: 30 AF XY: 0.00000691 AC XY: 5 AN XY: 723512

African (AFR) AF: 0.00 AC: 0 AN: 33364

American (AMR) AF: 0.0000672 AC: 3 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 85404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5190

European-Non Finnish (NFE) AF: 0.00000813 AC: 9 AN: 1106950

Other (OTH) AF: 0.00 AC: 0 AN: 59896

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151740 Hom.: 0 Cov.: 30 AF XY: 0.0000270 AC XY: 2 AN XY: 74072

African (AFR) AF: 0.00 AC: 0 AN: 41290

American (AMR) AF: 0.00 AC: 0 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67980

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		6.8
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.94
MutPred		0.82		Gain of ubiquitination at K249 (P = 0.0624)
MVP		0.81
MPC		0.41
ClinPred		1.0	D
GERP RS		5.6
gMVP		0.86
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs142416956; hg19: chr2-202700375;