9-21970934-T-C

Position:

chr9-21970934-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_000077.5(CDKN2A):c.425A>G(p.His142Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,612,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: -1.13

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. 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

BP4

Computational evidence support a benign effect (MetaRNN=0.070082694).

BS2

High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.425A>G	p.His142Arg	missense_variant	2/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4 linkuse as main transcript	c.*69A>G		3_prime_UTR_variant	2/3	ENST00000579755.2	NP_478102.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.425A>G	p.His142Arg	missense_variant	2/3	1	NM_000077.5	ENSP00000307101	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.*69A>G		3_prime_UTR_variant	2/3	1	NM_058195.4	ENSP00000462950		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

246972

Hom.:

AF XY:

0.00000746

AC XY:

AN XY:

134132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000271

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1460164

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

726462

show subpopulations

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:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Apr 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2023	The p.H142R variant (also known as c.425A>G), located in coding exon 2 of the CDKN2A gene, results from an A to G substitution at nucleotide position 425. The histidine at codon 142 is replaced by arginine, an amino acid with highly similar properties. This variant was previously detected as a germline alteration in a patient with multiple melanomas, who also harbored a pathogenic CDKN2A mutation and in an unrelated sporadic single melanoma patient (Pastorino et al. Pigment Cell Melanoma Res. 2008 Dec;21:700-9). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 23, 2022	This missense variant replaces histidine with arginine at codon 142 of the CDKN2A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant impairs protein interaction with the binding partners, leukemogenic potential, and CDK4/6 inhibitory function of the CDKN2A protein (PMID: 20522552, 28218424, 34369425). Most of the variant effect on protein function was reported to be mild. This variant has been reported in four individuals affected with melanoma (PMID: 18983535, 19158841, 21462282) and in an individual affected with acute lymphoblastic leukemia (PMID: 26104880). One of the individuals affected with melanoma was reported to carry a pathogenic variant in the same gene (PMID: 18983535). This variant has been identified in 3/246972 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 18, 2022	The CDKN2A c.425A>G; p.His142Arg variant (rs759922342) is reported in the literature in individuals affected with melanoma or acute lymphoblastic leukemia (Daniotti 2009, Miller 2011, Pastorino 2008, Xu 2015). However, at least one affected individual carrying this variant also carried a known pathogenic variant in CDKN2A (Pastorino 2008). The p.His142Arg variant is found on three chromosomes (3/246972 alleles) in the Genome Aggregation Database. The histidine at codon 142 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.441). However, functional studies of the variant protein suggest reduced tumor suppressor activity (Li 2022) and reduced interaction with binding partner proteins (Sun 2010). Due to conflicting information, the clinical significance of the p.His142Arg variant is uncertain at this time. References: Daniotti et al. Cutaneous melanoma in childhood and adolescence shows frequent loss of INK4A and gain of KIT. J Invest Dermatol. 2009; 129(7): 1759-1768. PMID: 19158841. Li C et al. The functional role of inherited CDKN2A variants in childhood acute lymphoblastic leukemia. Pharmacogenet Genomics. 2022 Feb 1;32(2):43-50. PMID: 34369425. Miller et al. Classifying variants of CDKN2A using computational and laboratory studies. Hum Mutat. 2011; 32(8): 900-911. PMID: 21462282. Pastorino et al. CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma. Pigment Cell Melanoma Res. 2008; 21(6): 700-709. PMID: 18983535. Sun et al. GRIM-19 and p16(INK4a) synergistically regulate cell cycle progression and E2F1-responsive gene expression. J Biol Chem. 2010; 285(36): 27545-27552. PMID: 20522552. Xu et al. Inherited coding variants at the CDKN2A locus influence susceptibility to acute lymphoblastic leukaemia in children. Nat Commun. 2015; 6:7553. PMID: 26104880. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with melanoma; however, one of these individuals also harbored a pathogenic CDKN2A variant, as well as in individual(s) with leukemia (Pastorino et al., 2008; Daniotti et al., 2009; Xu et al., 2015; Vergani et al., 2021; Li et al., 2022); This variant is associated with the following publications: (PMID: 26104880, 21462282, 8834170, 18983535, 9132280, 19158841, 21619050, 20522552, 34573422, 34426522, 34369425) -

Familial melanoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 142 of the CDKN2A (p16INK4a) protein (p.His142Arg). This variant is present in population databases (rs759922342, gnomAD 0.002%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia and/or melanoma (PMID: 18983535, 19158841, 21462282, 26104880). ClinVar contains an entry for this variant (Variation ID: 184564). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects CDKN2A (p16INK4a) function (PMID: 20522552, 34369425). 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

0.072

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Benign

-0.26

CADD

Benign

0.26

DANN

Benign

0.38

DEOGEN2

Benign

0.087

T;.;.;.;.;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.51

T;.;T;.;T;T;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.070

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N;N;N;N;N

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.67

N;.;N;.;.;.;.

REVEL

Uncertain

0.44

Sift

Benign

0.058

T;.;T;.;.;.;.

Sift4G

Benign

0.69

T;T;T;T;T;T;T

Polyphen

0.0

B;.;.;.;.;.;.

Vest4

0.26

MutPred

0.43

Gain of MoRF binding (P = 0.0165);.;Gain of MoRF binding (P = 0.0165);.;.;.;.;

MVP

0.60

MPC

0.50

ClinPred

0.050

GERP RS

-6.6

Varity_R

0.049

gMVP

0.50

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over