NM_000077.5:c.151-1G>C

Variant names:

• chr9-21971209-C-G
• rs730881677
• NM_000077.5:c.151-1G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000077.5(CDKN2A):​c.151-1G>C variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.27
• Publications: 21 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-21971209-C-G is Pathogenic according to our data. Variant chr9-21971209-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 182416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000077.5. 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.151-1G>C		splice_acceptor intron	N/A	NP_000068.1
	CDKN2A	NM_058195.4	MANE Plus Clinical	c.194-1G>C		splice_acceptor intron	N/A	NP_478102.2
	CDKN2A	NM_001195132.2		c.151-1G>C		splice_acceptor intron	N/A	NP_001182061.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDKN2A	ENST00000304494.10	TSL:1 MANE Select	c.151-1G>C		splice_acceptor intron	N/A	ENSP00000307101.5
	CDKN2A	ENST00000579755.2	TSL:1 MANE Plus Clinical	c.194-1G>C		splice_acceptor intron	N/A	ENSP00000462950.1
	CDKN2A	ENST00000498124.1	TSL:1	c.151-1G>C		splice_acceptor intron	N/A	ENSP00000418915.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Aug 20, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.151-1 G>C splice site variant in the CDKN2A gene destroys the canonical splice acceptor site in intron 1, and appears to cause aberrant splicing of both the p16(INK4a) and p14(ARF) transcripts leading to severely abnormal proteins (Prowse et al., 2003). In the family reported by Prowse et al., several confirmed CDKN2A variant carriers were reported to have multiple benign and malignant tumors including melanoma, neurofibromas, an osteochondroma, and early-onset breast cancer (although the relationship of the variant to the increased risk of breast cancer in the reported family is unknown).

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 26, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.151-1G>C intronic pathogenic mutation results from a G to C one nucleotide upstream from coding exon 2 of the CDKN2A gene. This variant has been observed in patients with personal and family histories of melanoma and/or other tumors such as neurofibromas and peripheral nerve sheath tumors (Petronzelli F et al. Genes Chromosomes Cancer 2001 Aug; 31(4):398-401; Sargen MR et al. Br. J. Dermatol. 2016 Oct;175(4):785-9; Hocevar M et al. Croat. Med. J. 2006 Dec;47(6):851-4; Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RNA studies have shown that this variant results in aberrant splicing (Petronzelli F et al. Genes Chromosomes Cancer 2001 Aug; 31(4):398-401; Prowse AH et al. J. Med. Genet. 2003 Aug; 40(8):e102). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Familial melanoma Pathogenic:1

Jun 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts with different open reading frames. Both transcripts have been analyzed. We report either the variant with the higher classification or default to the CDKN2A (p16INK4a) variant. This report therefore includes the details for the CDKN2A (p16INK4a) variant. This sequence change affects an acceptor splice site in intron 1 of the CDKN2A (p16INK4a) gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of melanoma-NST syndrome (PMID: 11433531, 12920094, 26876133). It has also been observed to segregate with disease in related individuals. This variant is also known as c.194-1G>C in CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 182416). Studies have shown that disruption of this splice site results in skipping of exon 2 and introduces a premature termination codon (PMID: 11433531, 12920094). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. The evidence indicates that this variant confers risk of developing CDKN2A (p16INK4a) and CDKN2A (p14ARF)-associated conditions.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.3
GERP RS		5.9
PromoterAI		0.12	Neutral
Mutation Taster		=30/270	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: -18
DS_AL_spliceai		1.0		Position offset: -1

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

Other links and lift over

dbSNP: rs730881677; hg19: chr9-21971208; COSMIC: COSV58708670; COSMIC: COSV58708670;