9-21974795-AGGCTCCATGCTGCTCCCCGCCGCC-A

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM4BS1_SupportingBS2

The NM_000077.5(CDKN2A):c.9_32delGGCGGCGGGGAGCAGCATGGAGCC(p.Ala4_Pro11del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000952 in 1,606,464 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000080 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 2.62

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 Likely_benign. Variant got -1 ACMG points.

PM1

In a chain Cyclin-dependent kinase inhibitor 2A (size 155) in uniprot entity CDN2A_HUMAN there are 42 pathogenic changes around while only 12 benign (78%) in NM_000077.5

PM4

Nonframeshift variant in NON repetitive region in NM_000077.5.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000243 (37/151972) while in subpopulation AMR AF= 0.0021 (32/15266). AF 95% confidence interval is 0.00153. There are 1 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 37 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.9_32delGGCGGCGGGGAGCAGCATGGAGCC	p.Ala4_Pro11del	disruptive_inframe_deletion	Exon 1 of 3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.194-3611_194-3588delGGCGGCGGGGAGCAGCATGGAGCC		intron_variant	Intron 1 of 2	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.9_32delGGCGGCGGGGAGCAGCATGGAGCC	p.Ala4_Pro11del	disruptive_inframe_deletion	Exon 1 of 3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755.2 link	c.194-3611_194-3588delGGCGGCGGGGAGCAGCATGGAGCC		intron_variant	Intron 1 of 2	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

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:

0.0000589

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000145

AC:

AN:

233942

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

129094

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000525

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad SAS exome

AF:

0.0000660

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000958

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.0000798

AC:

116

AN:

1454492

Hom.:

AF XY:

0.0000760

AC XY:

AN XY:

723908

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000493

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000581

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000720

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.000243

AC:

AN:

151972

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74232

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00210

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000155

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Melanoma-pancreatic cancer syndrome

Uncertain:3

Sep 13, 2016

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 20, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:2

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDKN2A c.9_32del24 (p.Ala4_Pro11del) results in an in-frame deletion that is predicted to remove 8 amino acids from the encoded protein. The variant allele was found at a frequency of 0.00015 in 233942 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma (0.00015 vs 0.0003), allowing no conclusion about variant significance. c.9_32del24 has been reported in the literature in individuals affected with Cutaneous Malignant Melanoma (Aitken_1999, Bishop_2002, Goldstein_2006, Goldstein_2007, Harland_2014, Wadt_2015, Cust_2011). However, these reports do not provide unequivocal conclusions about an association of the variant with Cutaneous Malignant Melanoma. The following publications have been ascertained in the context of this evaluation (PMID: 12072543, 17047042, 16905682, 19759551, 21325014, 25803691, 26976419, 10070944, 11159196, 25780468, 36243179, 35264596). ClinVar contains an entry for this variant (Variation ID: 216277). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

not provided

Uncertain:2

Nov 03, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In-frame deletion of 8 amino acid(s) in a non-repeat region; Observed in families with multiple cases of melanoma, demonstrating incomplete segregation with disease in at least one family, and in individuals with breast cancer (PMID: 10070944, 12072543, 17047042, 16905682, 20876876, 25780468, 25803691, 26976419, 35264596); In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17047042, 25780468, 10070944, 12072543, 16905682, 19759551, 25803691, 26976419, 20876876, 27196769, 21325014, 28830827, 35264596, 28765326, 27756164, 27960642, 18519632, 16818274, 11159196, 9166859, 7718873, 15146471, 37059229, 37833309, 36243179) -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Feb 21, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in a deletion of eight amino acids from the N-terminus of the CDKN2A (p16INK4A) protein. The residues deleted by this variant (p.Ala4_Pro11) are only present in human and two other non-human primate species. The mutant allele is a reference in other mammalian species (https://genome.ucsc.edu/). A functional study has shown that the mutant protein resulting from this variant retains normal protein function (PMID: 8668202). This variant has been reported in over ten individuals affected by melanoma (PMID: 10070944, 12072543, 16905682, 17047042, 19759551, 20876876, 21325014, 25780468, 25803691) and breast cancer (PMID: 26976419). This variant has also been identified in 36/265240 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and is particularly common in the Latino population (0.0512%, 18/35104 alleles). 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. -

Mar 11, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Melanoma and neural system tumor syndrome

Uncertain:1

Mar 13, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome

Uncertain:1

Jan 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial melanoma

Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.9_32del, results in the deletion of 8 amino acid(s) of the CDKN2A (p16INK4a) protein (p.Ala4_Pro11del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs751570838, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with breast cancer and melanoma (PMID: 12072543, 16905682, 17047042, 19759551, 20876876, 25780468, 25803691, 26976419). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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

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