rs1060501266

Positions:

• chr9-21968347-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.458-105A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,525,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CDKN2A NM_000077.5 intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: -3.10

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]

ENSG00000264545 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PP5: Variant 9-21968347-T-C is Pathogenic according to our data. Variant chr9-21968347-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 406715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21968347-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.458-105A>G		intron_variant		ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*102-105A>G		intron_variant		ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.458-105A>G		intron_variant		1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.*102-105A>G		intron_variant		1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152164 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: 0.0000117 AC: 16 AN: 1373396 Hom.: 0 AF XY: 0.0000117 AC XY: 8 AN XY: 684098

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000259

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74326

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

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2022	Non-canonical splice site variant demonstrated to result in aberrant splicing in a gene for which loss of function is a known mechanism of disease (Harland et al., 2001); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25685612, 16905682, 25780468, 26542317, 18612309, 22841127, 21614589, 21325014, 25023876, 11726555, 29215650, 23348723, 33322357, 15009729) -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 23, 2022	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This variant causes an A to G nucleotide substitution at the -105 position of intron 2 of the CDKN2A (p16INK4A) gene. This variant is also known as IVS2-105A>G in the literature. A non-quantitative RNA study has shown that this variant disrupts RNA splicing and causes aberrant retention of the entire, or almost all of, intron 2 sequence, resulting in the mutant transcripts that are much longer than the normal transcript (PMID: 11726555). This variant has been reported in over twenty individuals affected with familial cutaneous melanoma (PMID: 11726555, 15009729, 16905682, 22841127) and has been shown to segregate with disease in two families (PMID: 11726555). In addition, this variant has been observed to be de novo in an individual affected with multiple primary melanomas (PMID: 15009729). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 22, 2024	The c.458-105A>G intronic variant results from an A to G substitution 105 nucleotides upstream from coding exon 3 in the CDKN2A gene. This alteration has been reported in multiple melanoma families and was shown to segregate with disease, although there were unaffected carriers in these families (ages unknown) (Harland M et al. Hum Mol Genet. 2001 Nov;10:2679-86; Goldstein AM et al. Genes Chromosomes Cancer. 2005 Jun;43(2):128-36; Maubec E et al. J Am Acad Dermatol 2012 Dec;67(6):1257-64; Puig S et al. Genet Med. 2016 Jul;18(7):727-36). This alteration was confirmed to be a de novo alteration in an individual with eight cutaneous melanomas (Majore S et al. J Invest Dermatol. 2004 Feb;122(2):450-1). This alteration was shown to generate two alternate transcripts that retain all or part of intron 2 which encodes a stop codon. Although it was not empirically shown, if these transcripts escape nonsense-mediated mRNA decay, the authors predict that protein product is likely to be structurally and functionally similar to the wildtype protein as they will only differ by four C-terminal amino acids (Harland M et al. Hum Mol Genet. 2001 Nov;10:2679-86). Of note, this variant is also designated as "IVS2-105A>G" in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as a disease-causing mutation. -

Melanoma, cutaneous malignant, susceptibility to, 2 Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Sep 01, 2021	- -
risk factor, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -

Melanoma and neural system tumor syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 25, 2024

- -

Familial melanoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2025

This sequence change falls in intron 2 of the CDKN2A (p16INK4a) gene. It does not directly change the encoded amino acid sequence of the CDKN2A (p16INK4a) protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with cutaneous melanoma (PMID: 11726555, 15009729, 16905682, 22841127). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS2-105A>G. ClinVar contains an entry for this variant (Variation ID: 406715). Studies have shown that this variant results in inclusion of most or all of intron 2 in the CDKN2A (p16INK4a) mRNA and introduces a new termination codon (PMID: 11726555). However the mRNA is not expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.12
DANN	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060501266; hg19: chr9-21968346;