9-21970951-GC-GCC

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PVS1_StrongBS2

The NM_000077.5(CDKN2A):c.407dupG(p.Thr137HisfsTer5) 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 (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: -1.99

Variant links:

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 links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 1 pathogenic variants in the truncated region.

BS2

High AC in GnomAdExome4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.407dupG	p.Thr137HisfsTer5	frameshift_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.*51dupG		3_prime_UTR_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2	Q8N726-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 link	c.407dupG	p.Thr137HisfsTer5	frameshift_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755 link	c.*51dupG		3_prime_UTR_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

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:

AN:

1459566

Hom.:

Cov.:

AF XY:

0.00000826

AC XY:

AN XY:

726164

show subpopulations

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:

AN:

152216

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74368

show subpopulations

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:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 12, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). Based on the available evidence, the clinical significance of this variant remains unclear. -

not specified

Uncertain:1

Feb 16, 2021

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 28, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Jul 06, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Melanoma-pancreatic cancer syndrome

Uncertain:1

Sep 28, 2024

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A c.407dup (p.Thr137HisfsTer5) change duplicates one nucleotide to cause a frameshift and the creation of a premature stop codon. This variant is not predicted to result in nonsense mediated decay. This variant has been reported in a cohort of Italian families with melanoma (PMID: 19500876). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

Familial melanoma

Uncertain:1

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, 33436027). 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

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over