rs1064793953

chr9-21971067-G-Achr9-21971067-G-Cchr9-21971067-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_000077.5(CDKN2A):c.292C>T(p.His98Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000688 in 1,453,268 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H98Q) has been classified 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 P:1 U:5
• Conservation: PhyloP100: 3.82

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000077.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.38192967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5	c.292C>T	p.His98Tyr	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4	c.335C>T	p.Ala112Val	missense_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10	c.292C>T	p.His98Tyr	missense_variant	2/3	1	NM_000077.5	P2
CDKN2A	ENST00000579755.2	c.335C>T	p.Ala112Val	missense_variant	2/3	1	NM_058195.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1453268 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723272

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

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2016	Variant summary: The c.292C>T (p.His98Tyr) in CDKN2A gene is a missense change that involves a mildly conserved nucleotide and 4/5 in silico tools predict deleterious outcome. Despite that two independent studies have confirmed that H98Ywas acting not significantly different from wild-type when was tested in growth binding and phosphorylation assays. Both research groups agreed that H98y may represent a rare functional variant rather than causative mutation. The variant is absent from the control population dataset of ExAC. The variant was identified in a glioma tumor sample, but has not been reported by any reputable database/clinical laboratory. Taking together, the variant was classified as VUS until undeniable evidence confirming neutrality become available. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2015	This variant is denoted CDKN2A c.292C>T at the cDNA level, p.His98Tyr (H98Y) at the protein level, and results in the change of a Histidine to a Tyrosine (CAC>TAC). This variant is associated with growth suppression, RB phosphorylation, and CDK4 and CDK6 binding similar to wild type (Arap 1997, Ruas 1999, Miller 2011). CDKN2A His98Tyr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CDKN2A His98Tyr occurs at a position that is conserved in mammals and is located within the ANK3 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CDKN2A His98Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2022	The p.H98Y variant (also known as c.292C>T), located in coding exon 2 of the CDKN2A gene, results from a C to T substitution at nucleotide position 292. The histidine at codon 98 is replaced by tyrosine, an amino acid with similar properties. This alteration has been identified in glioblastoma cell line and functional studies have demonstrated the CDK4/CDK6 binding, growth suppression and effect on cell cycle arrest are similar to wild type (Arap W et al. Oncogene, 1997 Feb;14:603-9; Ruas M et al. Oncogene, 1999 Sep;18:5423-34). This amino acid position is 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. -

Squamous cell lung carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Familial melanoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

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 histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 98 of the CDKN2A (p16INK4a) protein (p.His98Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is also known as c.335C>T (p.Ala112Val) in the CDKN2A (p14ARF) transcript. ClinVar contains an entry for this variant (Variation ID: 419560). 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. Experimental studies have shown that this missense change does not substantially affect CDKN2A (p16INK4a) function (PMID: 9053859, 21462282). 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	Benign	0.26
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.032	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.61	T
MutationTaster	Benign	0.67	D;D;D;D;D;D;D;N;N;N;N;N
Sift4G	Benign	0.079	T;T
Vest4		0.38
MVP		0.99
ClinPred		0.88	D
GERP RS		5.9

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: rs1064793953; hg19: chr9-21971066; COSMIC: COSV58697396; COSMIC: COSV58697396;