12-55967036-A-C

Position:

• chr12-55967036-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000266970.9(CDK2):​c.28A>C​(p.Ile10Leu) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDK2 ENST00000266970.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.10

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]

(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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40792504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDK2	NM_001798.5	c.28A>C	p.Ile10Leu	missense_variant	1/7	ENST00000266970.9	NP_001789.2
CDK2	NM_052827.4	c.28A>C	p.Ile10Leu	missense_variant	1/6		NP_439892.2
CDK2	NM_001290230.2	c.28A>C	p.Ile10Leu	missense_variant	1/5		NP_001277159.1
CDK2	XM_011537732.2	c.28A>C	p.Ile10Leu	missense_variant	1/8		XP_011536034.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDK2	ENST00000266970.9	c.28A>C	p.Ile10Leu	missense_variant	1/7	1	NM_001798.5	ENSP00000266970	P1
	ENST00000554022.1	n.367T>G		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 28, 2023

The c.28A>C (p.I10L) alteration is located in exon 1 (coding exon 1) of the CDK2 gene. This alteration results from a A to C substitution at nucleotide position 28, causing the isoleucine (I) at amino acid position 10 to be replaced by a leucine (L). 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	Pathogenic	0.59
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	29
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T;T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.95	N;.;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.073	T;T;T;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.99	D;.;P;D
Vest4		0.54
MutPred		0.57		Gain of catalytic residue at Y15 (P = 0.007);Gain of catalytic residue at Y15 (P = 0.007);Gain of catalytic residue at Y15 (P = 0.007);Gain of catalytic residue at Y15 (P = 0.007);
MVP		0.77
MPC		1.9
ClinPred		0.94	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.70
gMVP		0.52

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: rs1336824730; hg19: chr12-56360820;