9-21970902-C-T

Variant names:

• chr9-21970902-C-T
• rs45476696
• NM_000077.5:c.457G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3 PP5

The NM_000077.5(CDKN2A):​c.457G>A​(p.Asp153Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D153H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDKN2A NM_000077.5 missense, splice_region
• Scores: Splicing: ADA: 0.9922
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 4.07
• Publications: 34 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-21970902-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 216035.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-21970902-C-T is Pathogenic according to our data. Variant chr9-21970902-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 532292.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.457G>A	p.Asp153Asn	missense_variant, splice_region_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.*101G>A		splice_region_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2
CDKN2A	NM_058195.4	c.*101G>A		3_prime_UTR_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.457G>A	p.Asp153Asn	missense_variant, splice_region_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.*101G>A		splice_region_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1
CDKN2A	ENST00000579755.2	c.*101G>A		3_prime_UTR_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000445 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 02, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D153N variant (also known as c.457G>A), located in coding exon 2 of the CDKN2A gene, results from a G to A substitution at nucleotide position 457. The amino acid change results in aspartic acid to asparagine at codon 153, an amino acid with highly similar properties. Of note, this variant is also known as c.*101G>A in the p14(ARF) isoform. This alteration was identified in individuals CDKN2A-associated disease (Ambry internal data; de Torre C et al. Melanoma Res 2010 Aug;20(4):342-8). However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Another alteration impacting the same donor site (c.457G>T) has been shown to result in aberrant splicing and has been detected in affected individuals (Ambry internal data; Rutter JL et al. Oncogene 2003 Jul; 22(28):4444-8; Loo JC et al. Oncogene 2003 Sep;22(41):6387-94.) Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Familial melanoma Uncertain:1

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 153 of the CDKN2A (p16INK4a) protein (p.Asp153Asn). This variant also falls at the last nucleotide of exon 2, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma (PMID: 20539244). ClinVar contains an entry for this variant (Variation ID: 532292). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.457G nucleotide in the CDKN2A (p16INK4a) gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12853981, 14508519, 24737347). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.45	T;.;.;T
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.37	T
PhyloP100		4.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.41	N;.;.;.
REVEL	Uncertain	0.52
Sift	Benign	0.26	T;.;.;.
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0080	B;.;.;.
Vest4		0.22
MutPred		0.37		Loss of phosphorylation at S152 (P = 0.1038);.;.;.;
MVP		0.92
ClinPred		0.48	T
GERP RS		3.3
PromoterAI		-0.067	Neutral
Varity_R		0.085
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.92
Splicevardb		3.0
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.73		Position offset: 0

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

Other links and lift over

dbSNP: rs45476696; hg19: chr9-21970901; COSMIC: COSV58690140; COSMIC: COSV58690140;