9-21968200-C-G

Variant names:

• chr9-21968200-C-G
• rs11515
• ENST00000380151.3:n.*423G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000380151.3(CDKN2A):​n.*423G>C 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 0.867 in 1,609,364 control chromosomes in the GnomAD database, including 605,137 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56366 hom., cov: 28)
  • Exomes 𝑓: 0.87 (548771 hom.)
• Consequence: CDKN2A ENST00000380151.3 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: -2.62
• Publications: 131 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 9-21968200-C-G is Benign according to our data. Variant chr9-21968200-C-G is described in ClinVar as Benign. ClinVar VariationId is 873162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

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.*29G>C		3_prime_UTR	Exon 3 of 3	NP_000068.1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.*144G>C		3_prime_UTR	Exon 3 of 3	NP_478102.2
	CDKN2A	NM_001195132.2		c.*193G>C		3_prime_UTR	Exon 4 of 4	NP_001182061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000380151.3	TSL:1	n.*423G>C		non_coding_transcript_exon	Exon 3 of 3	ENSP00000369496.3
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.*29G>C		3_prime_UTR	Exon 3 of 3	ENSP00000307101.5
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.*144G>C		3_prime_UTR	Exon 3 of 3	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.861 AC: 130666 AN: 151730 Hom.: 56326 Cov.: 28

Gnomad AFR AF: 0.837

Gnomad AMI AF: 0.881

Gnomad AMR AF: 0.885

Gnomad ASJ AF: 0.822

Gnomad EAS AF: 0.979

Gnomad SAS AF: 0.939

Gnomad FIN AF: 0.866

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.857

Gnomad OTH AF: 0.857

GnomAD2 exomes AF: 0.882 AC: 221546 AN: 251310 AF XY: 0.881

Gnomad AFR exome AF: 0.835

Gnomad AMR exome AF: 0.919

Gnomad ASJ exome AF: 0.828

Gnomad EAS exome AF: 0.978

Gnomad FIN exome AF: 0.871

Gnomad NFE exome AF: 0.855

Gnomad OTH exome AF: 0.867

GnomAD4 exome AF: 0.867 AC: 1263961 AN: 1457518 Hom.: 548771 Cov.: 33 AF XY: 0.868 AC XY: 629660 AN XY: 725386

African (AFR) AF: 0.829 AC: 27685 AN: 33384

American (AMR) AF: 0.915 AC: 40899 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.825 AC: 21533 AN: 26108

East Asian (EAS) AF: 0.981 AC: 38914 AN: 39678

South Asian (SAS) AF: 0.929 AC: 80039 AN: 86168

European-Finnish (FIN) AF: 0.873 AC: 46607 AN: 53414

Middle Eastern (MID) AF: 0.851 AC: 4812 AN: 5656

European-Non Finnish (NFE) AF: 0.859 AC: 951377 AN: 1108174

Other (OTH) AF: 0.865 AC: 52095 AN: 60216

GnomAD4 genome AF: 0.861 AC: 130763 AN: 151846 Hom.: 56366 Cov.: 28 AF XY: 0.863 AC XY: 64034 AN XY: 74194

African (AFR) AF: 0.837 AC: 34648 AN: 41378

American (AMR) AF: 0.885 AC: 13520 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 2852 AN: 3470

East Asian (EAS) AF: 0.979 AC: 5024 AN: 5134

South Asian (SAS) AF: 0.939 AC: 4506 AN: 4800

European-Finnish (FIN) AF: 0.866 AC: 9128 AN: 10544

Middle Eastern (MID) AF: 0.810 AC: 238 AN: 294

European-Non Finnish (NFE) AF: 0.857 AC: 58239 AN: 67934

Other (OTH) AF: 0.859 AC: 1810 AN: 2108

Alfa AF: 0.855 Hom.: 10219

Bravo AF: 0.861

Asia WGS AF: 0.941 AC: 3274 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Squamous cell lung carcinoma Uncertain:1

May 05, 2020

Faculté Pluridciplinaire Nador, Université Mohamed Premier

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing;in vivo

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.083
DANN	Benign	0.65
PhyloP100		-2.6
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: rs11515; hg19: chr9-21968199; COSMIC: COSV58682765; COSMIC: COSV58682765;