9-21974860-C-G

Position:

• chr9-21974860-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000579755.2(CDKN2A):​c.194-3652G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00147 in 1,515,778 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (4 hom.)
• Consequence: CDKN2A ENST00000579755.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.08

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 9-21974860-C-G is Benign according to our data. Variant chr9-21974860-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 548857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21974860-C-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 193 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.194-3652G>C		intron_variant		ENST00000579755.2	NP_478102.2
CDKN2A	NM_000077.5			upstream_gene_variant		ENST00000304494.10	NP_000068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.194-3652G>C		intron_variant		1	NM_058195.4	ENSP00000462950
CDKN2A	ENST00000304494.10			upstream_gene_variant		1	NM_000077.5	ENSP00000307101	P2

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152192 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00119 AC: 146 AN: 122584 Hom.: 0 AF XY: 0.00119 AC XY: 80 AN XY: 67288

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000475

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000210

Gnomad SAS exome AF: 0.000546

Gnomad FIN exome AF: 0.00170

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00149 AC: 2034 AN: 1363468 Hom.: 4 Cov.: 31 AF XY: 0.00151 AC XY: 1012 AN XY: 672112

Gnomad4 AFR exome AF: 0.000237

Gnomad4 AMR exome AF: 0.000437

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000282

Gnomad4 SAS exome AF: 0.000378

Gnomad4 FIN exome AF: 0.00183

Gnomad4 NFE exome AF: 0.00172

Gnomad4 OTH exome AF: 0.00103

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74476

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00141 Hom.: 0

Bravo AF: 0.00122

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	CDKN2A: BS1 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28830827, 28135145) -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 12, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 11, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2015	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 01, 2019	- -

Melanoma-pancreatic cancer syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 09, 2018	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Aug 15, 2023

- -

Familial melanoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 02, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.085
DANN	Benign	0.40

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: rs531597737; hg19: chr9-21974859;