rs200129494

Variant names:

• chr9-21974463-AC-A
• rs200129494
• ENST00000380151.3:n.*13delG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The ENST00000380151.3(CDKN2A):​n.*13delG variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,612,006 control chromosomes in the GnomAD database, including 44 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0096 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (23 hom.)
• Consequence: CDKN2A ENST00000380151.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.338
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 9-21974463-AC-A is Benign according to our data. Variant chr9-21974463-AC-A is described in ClinVar as Benign. ClinVar VariationId is 402524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00962 (1466/152326) while in subpopulation AFR AF = 0.0321 (1336/41564). AF 95% confidence interval is 0.0307. There are 21 homozygotes in GnomAd4. There are 666 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1466 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000380151.3. 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+214delG		intron	N/A	NP_000068.1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-3256delG		intron	N/A	NP_478102.2
	CDKN2A	NM_058197.5		c.*13delG		3_prime_UTR	Exon 1 of 3	NP_478104.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000380151.3	TSL:1	n.*13delG		non_coding_transcript_exon	Exon 1 of 3	ENSP00000369496.3
	CDKN2A	ENST00000380151.3	TSL:1	n.*13delG		3_prime_UTR	Exon 1 of 3	ENSP00000369496.3
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.150+214delG		intron	N/A	ENSP00000307101.5

Frequencies

GnomAD3 genomes AF: 0.00961 AC: 1463 AN: 152208 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.0322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00621

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00115 AC: 288 AN: 250770 AF XY: 0.000781

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.000841

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.00112 AC: 1640 AN: 1459680 Hom.: 23 Cov.: 31 AF XY: 0.000964 AC XY: 700 AN XY: 726170

African (AFR) AF: 0.0337 AC: 1128 AN: 33460

American (AMR) AF: 0.00264 AC: 118 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 60 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.0000937 AC: 8 AN: 85396

European-Finnish (FIN) AF: 0.0000752 AC: 4 AN: 53214

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5758

European-Non Finnish (NFE) AF: 0.000146 AC: 162 AN: 1111098

Other (OTH) AF: 0.00239 AC: 144 AN: 60322

GnomAD4 genome AF: 0.00962 AC: 1466 AN: 152326 Hom.: 21 Cov.: 32 AF XY: 0.00894 AC XY: 666 AN XY: 74490

African (AFR) AF: 0.0321 AC: 1336 AN: 41564

American (AMR) AF: 0.00621 AC: 95 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68024

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.000526 Hom.: 0

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.34
Mutation Taster		=100/0	polymorphism

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: rs200129494; hg19: chr9-21974462;