rs2518719

chr9-21970428-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. Variant has been reported in Lovd as Benign (no stars).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 9-21970428-A-G is Benign according to our data. Variant chr9-21970428-A-G is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.457+474T>C		intron_variant		ENST00000304494.10
CDKN2A	NM_058195.4	c.*101+474T>C		intron_variant		ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.457+474T>C		intron_variant		1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.*101+474T>C		intron_variant		1	NM_058195.4

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

Gnomad4 AFR exome AF: 0.125

Gnomad4 AMR exome AF: 0.0986

Gnomad4 ASJ exome AF: 0.132

Gnomad4 EAS exome AF: 0.000190

Gnomad4 SAS exome AF: 0.0381

Gnomad4 FIN exome AF: 0.0952

Gnomad4 NFE exome AF: 0.134

Gnomad4 OTH exome AF: 0.119

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

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.144

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.0348

Gnomad4 FIN AF: 0.100

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.148

Alfa AF: 0.128 Hom.: 397

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

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: rs2518719; hg19: chr9-21970427;