rs45456595

Variant names:

• chr9-21974641-C-G
• rs45456595
• NM_000077.5:c.150+37G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-21974641-C-G
• chr9-21974641-C-A
• chr9-21974641-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_058197.5(CDKN2A):​c.187G>C​(p.Gly63Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,614,214 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (7 hom.)
• Consequence: CDKN2A NM_058197.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:14 O:1
• Conservation: PhyloP100: -2.00
• Publications: 20 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: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Genomics England PanelApp
• 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 -9 ACMG points.

• BP6: Variant 9-21974641-C-G is Benign according to our data. Variant chr9-21974641-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 41573.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00202 (308/152346) while in subpopulation NFE AF = 0.00325 (221/68028). AF 95% confidence interval is 0.0029. There are 0 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 308 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058197.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_000077.5	MANE Select	c.150+37G>C		intron	N/A	NP_000068.1	P42771-1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3433G>C		intron	N/A	NP_478102.2	Q8N726-1
	CDKN2A	NM_058197.5		c.187G>C	p.Gly63Arg	missense	Exon 1 of 3	NP_478104.2	P42771-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.150+37G>C		intron	N/A	ENSP00000307101.5	P42771-1
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-3433G>C		intron	N/A	ENSP00000462950.1	Q8N726-1
	CDKN2A	ENST00000498124.1	TSL:1	c.150+37G>C		intron	N/A	ENSP00000418915.1	P42771-4

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 308 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000940

Gnomad AMI AF: 0.00879

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00202 AC: 507 AN: 250906 AF XY: 0.00213

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00350

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00268 AC: 3921 AN: 1461868 Hom.: 7 Cov.: 32 AF XY: 0.00273 AC XY: 1984 AN XY: 727240

African (AFR) AF: 0.000478 AC: 16 AN: 33478

American (AMR) AF: 0.00125 AC: 56 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000730 AC: 63 AN: 86254

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53402

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00326 AC: 3630 AN: 1112012

Other (OTH) AF: 0.00200 AC: 121 AN: 60396

GnomAD4 genome AF: 0.00202 AC: 308 AN: 152346 Hom.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74502

African (AFR) AF: 0.000938 AC: 39 AN: 41590

American (AMR) AF: 0.00189 AC: 29 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00295 Hom.: 1

Bravo AF: 0.00237

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	7	not provided (9)
-	1	2	Hereditary cancer-predisposing syndrome (3)
-	1	2	Melanoma-pancreatic cancer syndrome (3)
-	2	1	not specified (4)
-	-	1	CDKN2A-related disorder (1)
-	-	1	Familial melanoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_noAF	Benign	-0.75
CADD	Benign	1.1
DANN	Benign	0.41
PhyloP100		-2.0
PromoterAI		-0.052	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: -42

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45456595; hg19: chr9-21974640; COSMIC: COSV58719681;