rs3731217

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id 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/exons	MANE	UniProt
CDKN2A	NM_058195.4	c.193+9477T>G		intron_variant		ENST00000579755.2
LOC124902130	XR_007061436.1	n.7962T>G		non_coding_transcript_exon_variant	2/2
CDKN2A	NM_001363763.2	c.-4+10159T>G		intron_variant
CDKN2A	XM_047422597.1	c.-4+9885T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000579755.2	c.193+9477T>G		intron_variant		1	NM_058195.4
CDKN2A	ENST00000494262.5	c.-4+9220T>G		intron_variant		3
CDKN2A	ENST00000498628.6	c.-4+10159T>G		intron_variant		2
CDKN2A	ENST00000530628.2	c.193+9477T>G		intron_variant		5

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

Gnomad4 AFR AF: 0.0995

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.103

Gnomad4 FIN AF: 0.0997

Gnomad4 NFE AF: 0.138

Gnomad4 OTH AF: 0.145

Alfa AF: 0.134 Hom.: 2976

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 04, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.7
DANN	Benign	0.46

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: rs3731217; hg19: chr9-21984661; COSMIC: COSV64266724; COSMIC: COSV64266724;