rs2811710

chr9-21991924-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_058195.4(CDKN2A):c.193+2215G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.39 in 983,220 control chromosomes in the GnomAD database, including 77,739 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 0.46 (17719 hom., cov: 32)
  • Exomes 𝑓: 0.38 (60020 hom.)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.85

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]

LOC124902130 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.67 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_058195.4	c.193+2215G>A		intron_variant		ENST00000579755.2
LOC124902130	XR_007061436.1	n.700G>A		non_coding_transcript_exon_variant	2/2
CDKN2A	NM_001363763.2	c.-4+2897G>A		intron_variant
CDKN2A	XM_047422597.1	c.-4+2623G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000579755.2	c.193+2215G>A		intron_variant		1	NM_058195.4

Frequencies

GnomAD3 genomes AF: 0.461 AC: 70033 AN: 151832 Hom.: 17680 Cov.: 32

Gnomad AFR AF: 0.676

Gnomad AMI AF: 0.413

Gnomad AMR AF: 0.506

Gnomad ASJ AF: 0.416

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.337

Gnomad FIN AF: 0.335

Gnomad MID AF: 0.472

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.468

GnomAD4 exome AF: 0.377 AC: 313138 AN: 831270 Hom.: 60020 Cov.: 25 AF XY: 0.377 AC XY: 144835 AN XY: 383956

Gnomad4 AFR exome AF: 0.700

Gnomad4 AMR exome AF: 0.520

Gnomad4 ASJ exome AF: 0.403

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.345

Gnomad4 FIN exome AF: 0.341

Gnomad4 NFE exome AF: 0.370

Gnomad4 OTH exome AF: 0.387

GnomAD4 genome AF: 0.462 AC: 70141 AN: 151950 Hom.: 17719 Cov.: 32 AF XY: 0.459 AC XY: 34047 AN XY: 74248

Gnomad4 AFR AF: 0.676

Gnomad4 AMR AF: 0.506

Gnomad4 ASJ AF: 0.416

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.337

Gnomad4 FIN AF: 0.335

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.470

Alfa AF: 0.407 Hom.: 3624

Bravo AF: 0.487

Asia WGS AF: 0.366 AC: 1269 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.11
Dann	Benign	0.33

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: rs2811710; hg19: chr9-21991923; COSMIC: COSV64266736; COSMIC: COSV64266736;