chr9-21970951-G-GC

Position:

• chr9-21970951-G-GC

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_Strong BS2

The ENST00000304494.10(CDKN2A):​c.407dupG​(p.Thr137fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,611,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G136G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CDKN2A ENST00000304494.10 frameshift
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: -1.99

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.136 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• BS2: High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.407dupG	p.Thr137fs	frameshift_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*51dupG		3_prime_UTR_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.407dupG	p.Thr137fs	frameshift_variant	2/3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755	c.*51dupG		3_prime_UTR_variant	2/3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1459566 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726164

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000116

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74368

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 03, 2022	The c.407dupG variant, located in coding exon 2 of the CDKN2A gene, results from a duplication of G at nucleotide position 407, causing a translational frameshift with a predicted alternate stop codon (p.T137Hfs*5). This alteration occurs at the 3' terminus of theCDKN2A gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 20 amino acids of the protein. The exact functional effect of this alteration is unknown. This alteration has been reported in a cohort of 204 Italian melanoma families and was not seen in 200 control subjects (Bruno W et al. J Am Acad Dermatol, 2009 Nov;61:775-82). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 12, 2023	This variant inserts 1 nucleotide in exon 2 of the CDKN2A (p16INK4A) gene, creating a frameshift and premature translation stop signal. The mutant transcript is predicted to escape nonsense-mediated decay and expressed as a truncated protein missing the C-terminus of the ankyrin repeat domain. However the variant occurs after the last conserved helix and invariant Tyr-Leu (YL) motif (PMID: 8880901). To our knowledge, functional studies have not been reported for this variant. The variant has been reported in an individual affected with familial melanoma (PMID: 19500876) and an individual with an advanced colorectal adenoma (PMID: 33436027). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 16, 2021

This sequence change results in an amino acid frameshift and creates a premature stop codon 4 amino acids downstream of the change, p.Thr137Hisfs*5. This sequence change results in a stop codon at the 3' end of CDKN2A, is not expected to trigger nonsense-mediated mRNA decay and is expected to modify 4 amino acids and delete the last 16 amino acids of the resultant protein. This sequence change has been described in the gnomAD database with a low population frequency of 0.0020% (dbSNP rs748022323). This sequence change has been reported in a family affected with melanoma (PMID: 19500876) and was not identified in 200 controls. Due to the location of this variant and the prediction that it does not trigger nonsense mediated decay, and the lack of functional studies, the clinical significance of this variant remains unknown at this time. -

Melanoma and neural system tumor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

May 28, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 06, 2023

Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation as the last 20 amino acids are replaced with 4 different amino acids, although loss-of-function variants have not been reported downstream of this position in the protein; Identified in an individual with a personal and family history of melanoma (Bruno et al., 2009); This variant is associated with the following publications: (PMID: 19500876) -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change creates a premature translational stop signal (p.Thr137Hisfs*5) in the CDKN2A (p16INK4a) gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 20 amino acid(s) of the CDKN2A (p16INK4a) protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with melanoma (PMID: 19500876). ClinVar contains an entry for this variant (Variation ID: 483327). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs749588877; hg19: chr9-21970950;