9-21974219-A-G

Variant names:

• chr9-21974219-A-G
• rs3731239
• NM_000077.5:c.150+459T>C

Variant summary

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

The NM_000077.5(CDKN2A):​c.150+459T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 152,118 control chromosomes in the GnomAD database, including 6,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.26 (6490 hom., cov: 32)
• Consequence: CDKN2A NM_000077.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.922
• Publications: 63 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 9-21974219-A-G is Benign according to our data. Variant chr9-21974219-A-G is described in ClinVar as Benign. ClinVar VariationId is 1241937.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	NM_000077.5	MANE Select	c.150+459T>C		intron	N/A	NP_000068.1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3011T>C		intron	N/A	NP_478102.2
	CDKN2A	NM_001195132.2		c.150+459T>C		intron	N/A	NP_001182061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.150+459T>C		intron	N/A	ENSP00000307101.5
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-3011T>C		intron	N/A	ENSP00000462950.1
	CDKN2A	ENST00000498124.1	TSL:1	c.150+459T>C		intron	N/A	ENSP00000418915.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 38995 AN: 152000 Hom.: 6492 Cov.: 32

Gnomad AFR AF: 0.0648

Gnomad AMI AF: 0.214

Gnomad AMR AF: 0.212

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.371

Gnomad OTH AF: 0.245

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

GnomAD4 genome AF: 0.256 AC: 38988 AN: 152118 Hom.: 6490 Cov.: 32 AF XY: 0.257 AC XY: 19070 AN XY: 74336

African (AFR) AF: 0.0646 AC: 2684 AN: 41530

American (AMR) AF: 0.212 AC: 3237 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 916 AN: 3468

East Asian (EAS) AF: 0.126 AC: 650 AN: 5174

South Asian (SAS) AF: 0.224 AC: 1079 AN: 4818

European-Finnish (FIN) AF: 0.421 AC: 4433 AN: 10542

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.371 AC: 25219 AN: 67972

Other (OTH) AF: 0.246 AC: 519 AN: 2114

Alfa AF: 0.320 Hom.: 19565

Bravo AF: 0.233

Asia WGS AF: 0.196 AC: 683 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.7
DANN	Benign	0.25
PhyloP100		-0.92
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: rs3731239; hg19: chr9-21974218; COSMIC: COSV58718323; COSMIC: COSV58718323;