chr9-21974757-C-G

Position:

chr9-21974757-C-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong

The NM_000077.5(CDKN2A):c.71G>C(p.Arg24Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000808 in 1,609,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24C) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14O:1

Conservation

PhyloP100: 0.147

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 Pathogenic. Variant got 14 ACMG points.

PM1

In a repeat ANK 1 (size 29) in uniprot entity CDN2A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000077.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 9-21974757-C-G is Pathogenic according to our data. Variant chr9-21974757-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-21974757-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.71G>C	p.Arg24Pro	missense_variant	1/3	ENST00000304494.10	NP_000068.1
CDKN2A	NM_058195.4 linkuse as main transcript	c.194-3549G>C		intron_variant		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.71G>C	p.Arg24Pro	missense_variant	1/3	1	NM_000077.5	ENSP00000307101	P2	P42771-1
CDKN2A	ENST00000579755.2 linkuse as main transcript	c.194-3549G>C		intron_variant		1	NM_058195.4	ENSP00000462950		Q8N726-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151922

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:

0.0000169

AC:

AN:

236656

Hom.:

AF XY:

0.00000767

AC XY:

AN XY:

130408

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:

0.0000380

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000754

AC:

AN:

1457942

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

725456

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:

0.00000990

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151922

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74182

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

Bravo

AF:

0.00000378

ExAC

AF:

0.0000253

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Melanoma-pancreatic cancer syndrome

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	Department of Pediatrics, Memorial Sloan Kettering Cancer Center	Dec 15, 2020	- -
Pathogenic, no assertion criteria provided	research	Medical Genetics, Medical University Pleven	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 20, 2023	This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8570179, 11556834]. Functional studies indicate this variant impacts protein function [PMID: 17909018]. This variant is expected to disrupt protein structure [Myriad internal data]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 19, 2016	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 03, 2022	Published functional studies demonstrate a damaging effect: impaired binding to CDK4, impaired growth inhibition, and altered cellular localization (Monzon et al., 1998; Becker et al., 2001; McKenzie et al., 2010); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9516223, 10398427, 9823374, 9699728, 33945383, 29922827, 11595726, 21462282, 23190892, 16234564, 8570179, 9425228, 26845104, 11500805, 26775776, 15945100, 18843795, 26225579, 25356972, 26206375, 15235029, 28830827, 9328469, 15304099, 15146471, 9856841, 10390011, 12072543, 11815963, 21150883, 17218939, 21801156, 16905682, 18363633, 17047042, 26800492, 29506128, 31382929, 34308366, 32482799, 14646620, 30967399, 33050356, 30218143, 27535533, 11556834, 20340136) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2022	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/). This missense variant replaces arginine with proline at codon 24 of the CDKN2A (p16INK4A) protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown that this variant causes loss of p16INK4A binding to CDK4 and loss of cell cycle inhibition function (PMID: 17909018, 15945100, 19260062, 20340136, 11595726, 18843795). This variant has been reported in over 40 individuals affected with melanoma (PMID: 10390011, 15146471, 16905682, 17047042, 18363633, 21801156, 25780468, 26225579, 26775776, 33050356) and pancreatic cancer (PMID: 15146471, 16905682, 21150883, 25356972). A family study has shown that this variant segregates with melanoma in multiple related individuals (PMID: 9699728). This variant has been identified in 4/236656 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	University of Washington Department of Laboratory Medicine, University of Washington	Nov 20, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 22, 2024	The p.R24P pathogenic mutation (also known as c.71G>C), located in coding exon 1 of the CDKN2A gene, results from a G to C substitution at nucleotide position 71. The arginine at codon 24 is replaced by proline, an amino acid with dissimilar properties. This alteration has been detected in numerous familial melanoma kindreds with and without pancreatic cancer; in three such families, the alteration co-segregated with disease in 21 out of 23 affected individuals overall (Soufir N et al. Hum. Mol. Genet. 1998 Feb;7(2):209-16; Monzon J et al. N. Engl. J. Med. 1998 Mar;338(13):879-87; MacKie RM et al. J. Invest. Dermatol. 1998 Aug;111(2):269-72; Newton Bishop JA et al. Br. J. Cancer 1999 Apr;80(1-2):295-300; Holland EA et al. Genes Chromosomes Cancer 1999 Aug; 25(4):339-48; Della Torre G et al. Br. J. Cancer 2001 Sep;85(6):836-44; Stolarova L et al. Biomedicines. 2020 Oct;8(10):404). Functional studies have shown that p.R24P mutants have varying levels of decreased binding affinity to CDK4 while other assays measuring cell cycle arrest and oxidative regulation have demonstrated activity comparable to wild type (Miller PJ et al. Hum. Mutat. 2011 Aug;32(8):900-11; McKenzie HA et al. Hum. Mutat. 2010 Jun;31(6):692-701; Jenkins NC et al. J. Invest. Dermatol. 2013 Apr;133(4):1043-51; Monzon J et al. N. Engl. J. Med. 1998 Mar;338(13):879-87, Becker TM et al. Clin. Cancer Res. 2001 Oct;7(10):3282-8; Jones R et al. Cancer Res. 2007 Oct;67(19):9134-41). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Melanoma and neural system tumor syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 22, 2024

- -

Melanoma and neural system tumor syndrome;C1835044:Melanoma, cutaneous malignant, susceptibility to, 2;C1838547:Melanoma-pancreatic cancer syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Familial melanoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 24 of the CDKN2A (p16INK4a) protein (p.Arg24Pro). This variant is present in population databases (rs104894097, gnomAD 0.004%). This missense change has been observed in individual(s) with pancreatic cancer and multiple primary melanomas (PMID: 8570179, 9699728, 10390011, 15146471, 16905682, 17047042, 18363633, 21150883, 21801156, 25356972, 26225579). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9415). 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 affects CDKN2A (p16INK4a) function (PMID: 11595726, 15945100, 18843795, 20340136, 23190892). For these reasons, this variant has been classified as Pathogenic. -

Melanoma, cutaneous malignant, susceptibility to, 2

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Aug 01, 1998

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;T;.

Eigen

Benign

0.049

Eigen_PC

Benign

-0.13

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.74

T;T;T

M_CAP

Uncertain

0.24

MetaRNN

Pathogenic

0.89

D;D;D

MetaSVM

Benign

-0.73

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-2.1

N;.;N

REVEL

Uncertain

0.40

Sift

Benign

0.14

T;.;T

Sift4G

Benign

0.21

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.68

MutPred

0.67

Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);Loss of MoRF binding (P = 0.0099);

MVP

0.98

MPC

1.2

ClinPred

0.86

GERP RS

3.0

Varity_R

0.54

gMVP

0.96

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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