9-21971006-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000077.5(CDKN2A):c.353C>G(p.Ala118Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A118V) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.18

Publications

12 publications found

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 Gene-Disease associations (from GenCC):

melanoma, cutaneous malignant, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
melanoma-pancreatic cancer syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
familial atypical multiple mole melanoma syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
melanoma and neural system tumor syndrome
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

CDKN2A links:

ENSG00000264545 (HGNC:):

ENSG00000264545 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 40 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 chr9-21971006-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 406719.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDKN2A	NM_000077.5 link	c.353C>G	p.Ala118Gly	missense_variant	Exon 2 of 3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 link	c.396C>G	p.Gly132Gly	synonymous_variant	Exon 2 of 3	ENST00000579755.2	NP_478102.2	Q8N726-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 link	c.353C>G	p.Ala118Gly	missense_variant	Exon 2 of 3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755.2 link	c.396C>G	p.Gly132Gly	synonymous_variant	Exon 2 of 3	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000414

AC:

AN:

241548

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000914

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1456582

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724864

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5208

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111846

Other (OTH)

AF:

0.00

AC:

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

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

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;.;D;.;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.56

PhyloP100

9.2

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.7

D;.;.;D;.;.;.;.

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0020

D;.;.;D;.;.;.;.

Sift4G

Uncertain

0.0070

D;D;D;D;D;D;D;D

Polyphen

0.99

D;.;.;.;.;.;.;.

Vest4

0.83

MutPred

0.80

Gain of disorder (P = 0.0798);Gain of disorder (P = 0.0798);.;Gain of disorder (P = 0.0798);.;.;.;.;

MVP

0.98

MPC

1.2

ClinPred

0.97

GERP RS

5.9

PromoterAI

0.012

Neutral

(source)

Varity_R

0.58

gMVP

0.72

Mutation Taster

=5/95

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over