rs3087335

Variant names:

• chr12-55967052-A-C
• rs3087335
• NM_001798.5:c.44A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001798.5(CDK2):​c.44A>C​(p.Tyr15Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK2 NM_001798.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.31
• Publications: 18 publications found

Genes affected

CDK2 (HGNC:1771): (cyclin dependent kinase 2) This gene encodes a member of a family of serine/threonine protein kinases that participate in cell cycle regulation. The encoded protein is the catalytic subunit of the cyclin-dependent protein kinase complex, which regulates progression through the cell cycle. Activity of this protein is especially critical during the G1 to S phase transition. This protein associates with and regulated by other subunits of the complex including cyclin A or E, CDK inhibitor p21Cip1 (CDKN1A), and p27Kip1 (CDKN1B). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2014]

ENSG00000258554 (HGNC:):

PMEL (HGNC:10880): (premelanosome protein) This gene encodes a melanocyte-specific type I transmembrane glycoprotein. The encoded protein is enriched in melanosomes, which are the melanin-producing organelles in melanocytes, and plays an essential role in the structural organization of premelanosomes. This protein is involved in generating internal matrix fibers that define the transition from Stage I to Stage II melanosomes. This protein undergoes a complex pattern of prosttranslational processing and modification that is essential to the proper functioning of the protein. A secreted form of this protein that is released by proteolytic ectodomain shedding may be used as a melanoma-specific serum marker. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDK2	NM_001798.5	c.44A>C	p.Tyr15Ser	missense_variant	Exon 1 of 7	ENST00000266970.9	NP_001789.2
CDK2	NM_052827.4	c.44A>C	p.Tyr15Ser	missense_variant	Exon 1 of 6		NP_439892.2
CDK2	NM_001290230.2	c.44A>C	p.Tyr15Ser	missense_variant	Exon 1 of 5		NP_001277159.1
CDK2	XM_011537732.2	c.44A>C	p.Tyr15Ser	missense_variant	Exon 1 of 8		XP_011536034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDK2	ENST00000266970.9	c.44A>C	p.Tyr15Ser	missense_variant	Exon 1 of 7	1	NM_001798.5	ENSP00000266970.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;T;.
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;D;T
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.5	L;.;.;L
PhyloP100		9.3
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-8.5	D;D;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.89
MutPred		0.35		Gain of catalytic residue at Y15 (P = 0.001);Gain of catalytic residue at Y15 (P = 0.001);Gain of catalytic residue at Y15 (P = 0.001);Gain of catalytic residue at Y15 (P = 0.001);
MVP		0.94
MPC		2.6
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.034	Neutral
Varity_R		0.99
gMVP		0.86
Mutation Taster		=7/93	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: rs3087335; hg19: chr12-56360836;