rs121913381

Positions:

• chr9-21971037-C-A
• chr9-21971037-C-G
• chr9-21971037-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000077.5(CDKN2A):​c.322G>T​(p.Asp108Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 5.54

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 9-21971037-C-A is Pathogenic according to our data. Variant chr9-21971037-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182423.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.322G>T	p.Asp108Tyr	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.365G>T	p.Arg122Leu	missense_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10	c.322G>T	p.Asp108Tyr	missense_variant	2/3	1	NM_000077.5	ENSP00000307101	P2
CDKN2A	ENST00000579755.2	c.365G>T	p.Arg122Leu	missense_variant	2/3	1	NM_058195.4	ENSP00000462950

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1453704 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 723436

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial melanoma Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 09, 2020	This variant is not present in population databases (ExAC no frequency). 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. The p.Asp108Tyr variant has been reported to affect p16INK4a protein function (PMID: 12606942). The functional impact of p.Arg122Leu on p14ARF has not been tested. This variant has been observed in individuals with malignant melanoma (PMID: 17255954). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182423). This sequence change replaces aspartic acid with tyrosine at codon 108 of the p16INK4a protein (p.Asp108Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. Alternatively, this sequence change replaces arginine with leucine at codon 122 of the p14ARF protein (p.Arg122Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. The CDKN2A gene encodes two different proteins, p16INK4a and p14ARF, which are translated from alternative transcripts that have different open reading frames. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 13, 2024	ACMG criteria used: PS4, PM2, PP3. -

Neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2023

The p.D108Y variant (also known as c.322G>T), located in coding exon 2 of the CDKN2A gene, results from a G to T substitution at nucleotide position 322. The aspartic acid at codon 108 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with CDKN2A-related disease (Ambry internal data; Erlandson A et al. J. Invest. Dermatol., 2007 Jun;127:1465-7; Pissa M et al. Acta Oncol, 2021 Jul;60:888-896). Based on internal structural analysis, D108Y is more destabilizing to CDKN2A than internally pathogenic variants at the same position and nearby (Ambry internal data; Byeon IJ et al. Mol Cell 1998 Feb;1(3):421-31; Russo AA et al. Nature 1998 Sep;395(6699):237-43). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;T;.;.;.;.;T;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.66	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.11	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-8.2	D;.;.;D;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;.;.;D;.;.;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.77
MutPred		0.84		Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);.;Gain of MoRF binding (P = 0.0534);.;.;.;.;
MVP		0.99
MPC		1.4
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs121913381; hg19: chr9-21971036; COSMIC: COSV58682998; COSMIC: COSV58682998;