NM_000077.5:c.262G>C

Variant names:

• chr9-21971097-C-G
• rs121913384
• NM_000077.5:c.262G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000077.5(CDKN2A):​c.262G>C​(p.Glu88Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,574 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CDKN2A NM_000077.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 3.38

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 Uncertain_significance. Variant got 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5	c.262G>C	p.Glu88Gln	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4	c.305G>C	p.Gly102Ala	missense_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.262G>C	p.Glu88Gln	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5
CDKN2A	ENST00000579755.2	c.305G>C	p.Gly102Ala	missense_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452574 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723010

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Feb 14, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E88Q variant (also known as c.262G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 262. The glutamic acid at codon 88 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in a proband with melanoma as well as in an unaffected family member. The affected proband was also found to have a pathogenic frameshift mutation in the CDKN2A gene that was not present in the unaffected relative (Levanat S et al. Croat Med J, 2003 Aug;44:418-24). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Mar 02, 2018

Quest Diagnostics Nichols Institute San Juan Capistrano

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

May 14, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial melanoma Uncertain:1

Jun 02, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

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 replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 88 of the CDKN2A (p16INK4a) protein (p.Glu88Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with melanoma who also carries a pathogenic variant in CDKN2A (PMID: 12950144). This variant is also known as c.305G>C (p.Gly102Ala) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 619828). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;.;.;.;.;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;T;.;D;.;T;T;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.56	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.38	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.5	N;.;.;N;.;.;.;.
REVEL	Uncertain	0.46
Sift	Benign	0.12	T;.;.;D;.;.;.;.
Sift4G	Benign	0.45	T;T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;.;.;.;.;.
Vest4		0.36
MutPred		0.32		Gain of MoRF binding (P = 0.0862);Gain of MoRF binding (P = 0.0862);.;Gain of MoRF binding (P = 0.0862);.;.;.;.;
MVP		0.96
MPC		1.2
ClinPred		0.90	D
GERP RS		5.9
Varity_R		0.29
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913384; hg19: chr9-21971096;