9-21973423-G-T

Variant names:

• chr9-21973423-G-T
• rs2811708
• NM_000077.5:c.150+1255C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000077.5(CDKN2A):​c.150+1255C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.248 in 151,872 control chromosomes in the GnomAD database, including 4,738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.25 (4738 hom., cov: 32)
• Consequence: CDKN2A NM_000077.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.892
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 9-21973423-G-T is Benign according to our data. Variant chr9-21973423-G-T is described in ClinVar as [Benign]. Clinvar id is 254882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.150+1255C>A		intron_variant	Intron 1 of 2	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.194-2215C>A		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.150+1255C>A		intron_variant	Intron 1 of 2	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.194-2215C>A		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.248 AC: 37647 AN: 151754 Hom.: 4734 Cov.: 32

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.211

Gnomad SAS AF: 0.161

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.314

Gnomad NFE AF: 0.261

Gnomad OTH AF: 0.267

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.248 AC: 37691 AN: 151872 Hom.: 4738 Cov.: 32 AF XY: 0.244 AC XY: 18124 AN XY: 74206

African (AFR) AF: 0.253 AC: 10477 AN: 41412

American (AMR) AF: 0.211 AC: 3217 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 1011 AN: 3466

East Asian (EAS) AF: 0.211 AC: 1093 AN: 5174

South Asian (SAS) AF: 0.161 AC: 774 AN: 4812

European-Finnish (FIN) AF: 0.229 AC: 2403 AN: 10496

Middle Eastern (MID) AF: 0.324 AC: 94 AN: 290

European-Non Finnish (NFE) AF: 0.261 AC: 17738 AN: 67938

Other (OTH) AF: 0.270 AC: 568 AN: 2100

Alfa AF: 0.243 Hom.: 4295

Bravo AF: 0.250

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma-pancreatic cancer syndrome Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma, cutaneous malignant, susceptibility to, 2 Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	2.2
DANN	Benign	0.40
PhyloP100		-0.89
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: rs2811708; hg19: chr9-21973422;