rs3731217

Variant names:

• chr9-21984662-A-C
• rs3731217
• NM_058195.4:c.193+9477T>G

Your query was ambiguous. Multiple possible variants found:

• chr9-21984662-A-C
• chr9-21984662-A-G
• chr9-21984662-A-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_058195.4(CDKN2A):​c.193+9477T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.124 in 151,962 control chromosomes in the GnomAD database, including 1,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.12 (1273 hom., cov: 32)
• Consequence: CDKN2A NM_058195.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.282
• Publications: 88 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

LOC124902130 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-21984662-A-C is Benign according to our data. Variant chr9-21984662-A-C is described in ClinVar as Benign. ClinVar VariationId is 1170366.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_058195.4	c.193+9477T>G		intron_variant	Intron 1 of 2	ENST00000579755.2	NP_478102.2
LOC124902130	XR_007061436.1	n.7962T>G		non_coding_transcript_exon_variant	Exon 2 of 2
CDKN2A	NM_001363763.2	c.-4+10159T>G		intron_variant	Intron 1 of 2		NP_001350692.1
CDKN2A	XM_047422597.1	c.-4+9885T>G		intron_variant	Intron 1 of 2		XP_047278553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000579755.2	c.193+9477T>G		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.124 AC: 18771 AN: 151844 Hom.: 1271 Cov.: 32

Gnomad AFR AF: 0.0996

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0997

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.140

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

GnomAD4 genome AF: 0.124 AC: 18785 AN: 151962 Hom.: 1273 Cov.: 32 AF XY: 0.121 AC XY: 8955 AN XY: 74292

African (AFR) AF: 0.0995 AC: 4132 AN: 41528

American (AMR) AF: 0.108 AC: 1641 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.143 AC: 496 AN: 3464

East Asian (EAS) AF: 0.195 AC: 1008 AN: 5176

South Asian (SAS) AF: 0.103 AC: 499 AN: 4828

European-Finnish (FIN) AF: 0.0997 AC: 1056 AN: 10592

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9355 AN: 67804

Other (OTH) AF: 0.145 AC: 306 AN: 2106

Alfa AF: 0.133 Hom.: 6226

Bravo AF: 0.126

Asia WGS AF: 0.136 AC: 472 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial melanoma Benign:1

Dec 04, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.7
DANN	Benign	0.46
PhyloP100		0.28
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: rs3731217; hg19: chr9-21984661; COSMIC: COSV64266724; COSMIC: COSV64266724;