9-21970980-C-G

Position:

chr9-21970980-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000077.5(CDKN2A):c.379G>C(p.Ala127Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,444 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A127S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 2.90

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:

CDKN2A (HGNC:):

CDKN2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-21970980-C-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

PP5

Variant 9-21970980-C-G is Pathogenic according to our data. Variant chr9-21970980-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 571866.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDKN2A	NM_000077.5 linkuse as main transcript	c.379G>C	p.Ala127Pro	missense_variant	2/3	ENST00000304494.10	NP_000068.1	P42771-1K7PML8
CDKN2A	NM_058195.4 linkuse as main transcript	c.*23G>C		3_prime_UTR_variant	2/3	ENST00000579755.2	NP_478102.2	Q8N726-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDKN2A	ENST00000304494.10 linkuse as main transcript	c.379G>C	p.Ala127Pro	missense_variant	2/3	1	NM_000077.5	ENSP00000307101.5		P42771-1
CDKN2A	ENST00000579755 linkuse as main transcript	c.*23G>C		3_prime_UTR_variant	2/3	1	NM_058195.4	ENSP00000462950.1		Q8N726-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000409

AC:

AN:

244500

Hom.:

AF XY:

0.00000751

AC XY:

AN XY:

133184

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:

0.00000907

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458444

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725684

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 25, 2024	The p.A127P variant (also known as c.379G>C), located in coding exon 2 of the CDKN2A gene, results from a G to C substitution at nucleotide position 379. The alanine at codon 127 is replaced by proline, an amino acid with highly similar properties. This variant was reported in multiple individuals with features consistent with Melanoma-pancreatic cancer syndrome (Lynch HT et al. Cancer. 2002 Jan; 94(1):84-96; Pastorino L et al. Pigment Cell Melanoma Res. 2008 Dec; 21(6):700-9; Helsing P et al. Genes Chromosomes Cancer. 2008 Feb; 47(2):175-84; Levin T et al. Fam. Cancer. 2017 04;16:257-265). A functional study reported this variant as deleterious based on in-vitro assessment of impact on proliferation in human pancreatic cancer cell lines (Kimura H et al. Elife, 2022 Jan;11). This variant has been observed in at least one individual with a personal and/or family history that is consistent with Melanoma-pancreatic cancer syndrome (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 01, 2023	The CDKN2A locus encodes two different gene products, p16INK4a and p14ARF (https://www.ncbi.nlm.nih.gov/books/NBK7030/ ). This missense variant replaces alanine with proline at codon 127 of the CDKN2A (p16INK4A) protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies using cell proliferation assays and cell cycle analysis reported this variant as functionally deleterious (PMID: 35001868). This variant has been reported in at least ten individuals affected with melanoma (PMID: 11815963, 18023021, 18983535, 21462282, 22804906, 26775776, 27804060, 30274933, 30967399) and pancreatic cancer (PMID: 11815963; Color data). Positive family history has been reported for most of these individuals. This variant has been shown to segregate with disease in a family affected with late-onset pancreatic cancer and cutaneous malignant melanoma (3 informative meiosis, PMID: 11815963). This variant is rare in the general population and has been identified in 1/244500 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Melanoma and neural system tumor syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 13, 2022

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2023

Published functional studies show an impact on cell proliferation comparable to other known pathogenic CDKN2A variants (Kimura et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29922827, 15146471, 21462282, 11815963, 18023021, 18983535, 22804906, 35777164, 30967399, 30274933, 27804060, 35001868) -

Melanoma-pancreatic cancer syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 09, 2023

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35001868]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18983535, 18023021, 21462282]. -

Familial melanoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 09, 2022

This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 127 of the CDKN2A (p16INK4a) protein (p.Ala127Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with melanoma and pancreatic cancer (PMID: 11815963, 18023021, 18983535, 21462282, 22804906). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 571866). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

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

Eigen

Benign

0.14

Eigen_PC

Benign

-0.044

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.87

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

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.89

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

MetaSVM

Uncertain

-0.051

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-2.5

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

REVEL

Uncertain

0.44

Sift

Uncertain

0.0090

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

Sift4G

Uncertain

0.057

T;D;D;T;D;D;D;D

Polyphen

1.0

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

Vest4

0.80

MutPred

0.63

Loss of MoRF binding (P = 0.0601);Loss of MoRF binding (P = 0.0601);.;Loss of MoRF binding (P = 0.0601);.;.;.;.;

MVP

0.98

MPC

1.4

ClinPred

0.94

GERP RS

4.9

Varity_R

0.64

gMVP

0.86

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