2-201822872-A-G

Position:

• chr2-201822872-A-G

Variant summary

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

The NM_001366386.2(CDK15):​c.512A>G​(p.Lys171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDK15 NM_001366386.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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]

CDK15 (HGNC:):

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=0.10446948).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK15	NM_001366386.2	c.512A>G	p.Lys171Arg	missense_variant	5/14	ENST00000652192.3	NP_001353315.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK15	ENST00000652192.3	c.512A>G	p.Lys171Arg	missense_variant	5/14		NM_001366386.2	ENSP00000498608.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460132 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 726462

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2024

The c.359A>G (p.K120R) alteration is located in exon 5 (coding exon 4) of the CDK15 gene. This alteration results from a A to G substitution at nucleotide position 359, causing the lysine (K) at amino acid position 120 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.99
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.017
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.83	.;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.33	.;.;N;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.74	N;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.33	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Vest4		0.30
MutPred		0.39		.;.;Loss of methylation at K171 (P = 0.0174);Loss of methylation at K171 (P = 0.0174);
MVP		0.11
MPC		0.051
ClinPred		0.73	D
GERP RS		4.3
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs1696294748; hg19: chr2-202687595;