rs2518719

Variant names:

• chr9-21970428-A-G
• rs2518719
• NM_000077.5:c.457+474T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000077.5(CDKN2A):​c.457+474T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 350,418 control chromosomes in the GnomAD database, including 2,782 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1294 hom., cov: 32)
  • Exomes 𝑓: 0.11 (1488 hom.)
• Consequence: CDKN2A NM_000077.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• melanoma, cutaneous malignant, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• melanoma-pancreatic cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial atypical multiple mole melanoma syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• melanoma and neural system tumor syndrome

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000264545 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.457+474T>C		intron_variant	Intron 2 of 2	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*101+474T>C		intron_variant	Intron 2 of 2	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.457+474T>C		intron_variant	Intron 2 of 2	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.*101+474T>C		intron_variant	Intron 2 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18634 AN: 152072 Hom.: 1293 Cov.: 32

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.000771

Gnomad SAS AF: 0.0352

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.144

GnomAD4 exome AF: 0.110 AC: 21838 AN: 198228 Hom.: 1488 Cov.: 0 AF XY: 0.106 AC XY: 10546 AN XY: 99284

African (AFR) AF: 0.125 AC: 860 AN: 6888

American (AMR) AF: 0.0986 AC: 701 AN: 7110

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 1027 AN: 7776

East Asian (EAS) AF: 0.000190 AC: 3 AN: 15798

South Asian (SAS) AF: 0.0381 AC: 702 AN: 18404

European-Finnish (FIN) AF: 0.0952 AC: 616 AN: 6468

Middle Eastern (MID) AF: 0.108 AC: 103 AN: 956

European-Non Finnish (NFE) AF: 0.134 AC: 16264 AN: 121650

Other (OTH) AF: 0.119 AC: 1562 AN: 13178

GnomAD4 genome AF: 0.123 AC: 18646 AN: 152190 Hom.: 1294 Cov.: 32 AF XY: 0.118 AC XY: 8794 AN XY: 74402

African (AFR) AF: 0.127 AC: 5263 AN: 41520

American (AMR) AF: 0.108 AC: 1659 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 500 AN: 3470

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5178

South Asian (SAS) AF: 0.0348 AC: 168 AN: 4824

European-Finnish (FIN) AF: 0.100 AC: 1062 AN: 10608

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9383 AN: 67986

Other (OTH) AF: 0.148 AC: 312 AN: 2108

Alfa AF: 0.131 Hom.: 508

Bravo AF: 0.127

Asia WGS AF: 0.0500 AC: 173 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.030
DANN	Benign	0.21
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs2518719; hg19: chr9-21970427;