9-21970986-C-G

Position:

chr9-21970986-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The NM_000077.5(CDKN2A):c.373G>C(p.Asp125His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000353 in 1,610,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. D125E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:2

Conservation

PhyloP100: 0.313

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 -5 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain in NM_000077.5

BP4

Computational evidence support a benign effect (MetaRNN=0.15414613).

BP6

Variant 9-21970986-C-G is Benign according to our data. Variant chr9-21970986-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41577.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=10, Likely_benign=2}.

BS2

High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.373G>C	p.Asp125His	missense_variant	2/3	ENST00000304494.10
CDKN2A	NM_058195.4 linkuse as main transcript	c.*17G>C		3_prime_UTR_variant	2/3	ENST00000579755.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.373G>C	p.Asp125His	missense_variant	2/3	1	NM_000077.5	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.*17G>C		3_prime_UTR_variant	2/3	1	NM_058195.4		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000984

AC:

AN:

243848

Hom.:

AF XY:

0.000105

AC XY:

AN XY:

132914

show subpopulations

Gnomad AFR exome

AF:

0.000127

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:

0.000182

Gnomad OTH exome

AF:

0.000331

GnomAD4 exome

AF:

0.000371

AC:

541

AN:

1458052

Hom.:

Cov.:

AF XY:

0.000371

AC XY:

269

AN XY:

725502

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

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:

0.000470

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.000184

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74520

show subpopulations

Gnomad4 AFR

AF:

0.000120

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:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000354

Hom.:

Bravo

AF:

0.000189

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 20, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with melanoma, pancreatic cancer, and other cancers (Holland et al., 1999; Bishop et al., 2002; Begg et al., 2005; Orlow et al., 2007; Capanu et al., 2008; Council et al., 2009; Cust et al., 2011; Xu et al., 2015; Hu et al., 2016); This variant is associated with the following publications: (PMID: 10398427, 16234564, 17218939, 16896043, 25780468, 21325014, 20707869, 21462282, 26104880, 12072543, 22703879, 23819521, 26483394, 28822769, 28135145, 15146471, 19320745, 25186627, 29641532, 18335566, 32191290, 35001868, 34369425) -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 07, 2022	The frequency of this variant in the general population, 0.0002 (25/125522 chromosomes in European (Non-Finnish) subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in multiple individuals with melanoma as well as in unaffected controls (PMIDs: 10398427 (1999), 16234564 (2005), 19320745 (2009), 21325014 (2011), 25780468 (2014), and 29641532 (2018)). Additionally, it has been reported in affected individuals with childhood leukemia (PMID:26104880 (2015)), breast cancer (PMID: 25186627 (2015)), pancreatic cancer (PMID: 26483394 (2016)), osteosarcoma (PMID: 32191290 (2020)), and colorectal cancer (PMIDs: 28135145 (2017) and 28944238 (2017)). Published functional studies have reported inconclusive results on the effect this variant on CDK2NA protein function (PMID: 35001868 (2022), 34369425 (2022)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 18, 2017	- -

Melanoma-pancreatic cancer syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 28, 2021	The CDKN2A c.373G>C (p.Asp125His) missense change has a maximum subpopulation frequency of 0.020% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/9-21970985-C-G). Six of six in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in two families where at least two affected individuals in each family harbored the variant (PP1; PMID: 32989607), in an individual with a first-degree relative with melanoma (PS4_supporting; PMID: 12072543), as well as in three individuals with presumed sporadic melanoma (PMID: 17218939). In addition, it has been reported in one individual with pancreatic cancer (PMID: 26483394), three individuals with osteosarcoma (PMID: 32191290), two individuals with acute lymphoblastic leukemia (PMID: 26104880), and one individual with colorectal cancer (PMID: 28944238). It has also been reported in a total of three non-cancer control subjects (PMID: 27640074, 29641532). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria applied: PS4_supporting, PP1, BP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Aug 24, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 20, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 12, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 25, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 08, 2016	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 20, 2024	Variant summary: CDKN2A c.373G>C (p.Asp125His) results in a non-conservative amino acid change located in the Ankyrin repeat-containing domain (IPR020683) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00035 in 1612370 control chromosomes, predominantly at a frequency of 0.00046 within the Non-Finnish European subpopulation in the gnomAD database (v4.0.0). The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.5 fold the estimated maximal expected allele frequency for a pathogenic variant in CDKN2A causing Cutaneous Malignant Melanoma phenotype (0.0003), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.373G>C has been reported in the literature in multiple isolated reports of individuals affected with cutaneous/malignant/familial melanoma, colorectal cancer, breast cancer, childhood B-ALL, and among individuals in a study of patients enrolled in the Mayo Clinic Pancreatic Cancer patient registry (example, Begg_2005, Berwick_2006, Yurgelun_2017, Tung_2015, Xu_2015). One study examining the prevalence and predictors of germline CDKN2A mutations in melanoma cases from Australia, Spain and the UK reported this variant as "non-pathogenic" (Harland_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Cutaneous Malignant Melanoma. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Kimura_2022, Li_2022). The following publications have been ascertained in the context of this evaluation (PMID: 21462282, 25780468, 25186627, 26483394, 16896043, 18335566, 17218939, 12072543, 16234564, 19320745, 15146471, 26104880, 28135145, 27756164, 27960642, 28765326, 9166859, 16818274, 18519632, 7718873, 29758216, 10398427, 35001868, 34369425). ClinVar contains an entry for this variant (Variation ID: 41577). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Familial melanoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

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 aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 125 of the CDKN2A (p16INK4a) protein (p.Asp125His). This variant is present in population databases (rs146179135, gnomAD 0.02%). This missense change has been observed in individual(s) with melanoma and/or pancreatic cancer (PMID: 10398427, 12072543, 17218939, 19320745, 25780468, 26483394). ClinVar contains an entry for this variant (Variation ID: 41577). 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 histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

0.31

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Uncertain

0.46

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

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.72

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

M_CAP

Benign

0.064

MetaRNN

Benign

0.15

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

MetaSVM

Benign

-0.86

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.5

N;.;.;D;.;.;.;.

REVEL

Uncertain

0.37

Sift

Benign

0.050

D;.;.;T;.;.;.;.

Sift4G

Benign

0.13

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

Polyphen

0.0040

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

Vest4

0.30

MVP

0.85

MPC

0.49

ClinPred

0.033

GERP RS

1.7

Varity_R

0.18

gMVP

0.68

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

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