9-21971208-C-G

Position:

• chr9-21971208-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BS2_Supporting

The NM_000077.5(CDKN2A):​c.151G>C​(p.Val51Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000346 in 1,445,136 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense, splice_region
• Scores: Splicing: ADA: 0.9763
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.57

Genes affected

CDKN2A (HGNC:1787): (cyclin dependent kinase inhibitor 2A) This gene generates several transcript variants which differ in their first exons. At least three alternatively spliced variants encoding distinct proteins have been reported, two of which encode structurally related isoforms known to function as inhibitors of CDK4 kinase. The remaining transcript includes an alternate first exon located 20 Kb upstream of the remainder of the gene; this transcript contains an alternate open reading frame (ARF) that specifies a protein which is structurally unrelated to the products of the other variants. This ARF product functions as a stabilizer of the tumor suppressor protein p53 as it can interact with, and sequester, the E3 ubiquitin-protein ligase MDM2, a protein responsible for the degradation of p53. In spite of the structural and functional differences, the CDK inhibitor isoforms and the ARF product encoded by this gene, through the regulatory roles of CDK4 and p53 in cell cycle G1 progression, share a common functionality in cell cycle G1 control. This gene is frequently mutated or deleted in a wide variety of tumors, and is known to be an important tumor suppressor gene. [provided by RefSeq, Sep 2012]

CDKN2A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a repeat ANK 2 (size 28) in uniprot entity CDN2A_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.151G>C	p.Val51Leu	missense_variant, splice_region_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194G>C	p.Gly65Ala	missense_variant, splice_region_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.151G>C	p.Val51Leu	missense_variant, splice_region_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194G>C	p.Gly65Ala	missense_variant, splice_region_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000182 AC: 4 AN: 220322 Hom.: 0 AF XY: 0.0000326 AC XY: 4 AN XY: 122612

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000133

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1445136 Hom.: 0 Cov.: 31 AF XY: 0.00000695 AC XY: 5 AN XY: 719316

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: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000167 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2024

The p.V51L variant (also known as c.151G>C) is located in coding exon 2 of the CDKN2A gene. The valine at codon 51 is replaced by leucine, an amino acid with highly similar properties. This change occurs in the first base pair of coding exon 2. Of note, this alteration is also known as c.194G>C (p.G65A)in the p14(ARF) isoform. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.59	.;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Uncertain	0.46	D
PROVEAN	Pathogenic	-5.1	.;D
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.49
MVP		0.97
ClinPred		0.95	D
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.84
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: rs762630679; hg19: chr9-21971207;