9-21971189-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2

The NM_000077.5(CDKN2A):​c.170C>A​(p.Ala57Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000689 in 1,597,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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: 0.0000062 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

4
14

Clinical Significance

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

Conservation

PhyloP100: 1.96
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1
In a repeat ANK 2 (size 28) in uniprot entity CDN2A_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_000077.5
BP4
Computational evidence support a benign effect (MetaRNN=0.27536967).
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00000623 (9/1445364) while in subpopulation MID AF= 0.000698 (4/5730). AF 95% confidence interval is 0.000238. There are 0 homozygotes in gnomad4_exome. There are 4 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDKN2ANM_000077.5 linkc.170C>A p.Ala57Asp missense_variant Exon 2 of 3 ENST00000304494.10 NP_000068.1 P42771-1K7PML8
CDKN2ANM_058195.4 linkc.213C>A p.Arg71Arg 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
CDKN2AENST00000304494.10 linkc.170C>A p.Ala57Asp missense_variant Exon 2 of 3 1 NM_000077.5 ENSP00000307101.5 P42771-1
CDKN2AENST00000579755.2 linkc.213C>A p.Arg71Arg synonymous_variant Exon 2 of 3 1 NM_058195.4 ENSP00000462950.1 Q8N726-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152234
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000908
AC:
2
AN:
220150
Hom.:
0
AF XY:
0.00000815
AC XY:
1
AN XY:
122640
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000295
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:
0.0000101
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000623
AC:
9
AN:
1445364
Hom.:
0
Cov.:
31
AF XY:
0.00000556
AC XY:
4
AN XY:
719474
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000225
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152234
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000295
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000836
AC:
1

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:2
Aug 28, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 aspartic acid at codon 57 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early-onset rectal cancer (PMID: 35029067) and in an individual unaffected with cancer (PMID: 29641532). This variant has been identified in 2/220150 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. -

Jan 27, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.A57D variant (also known as c.170C>A), located in coding exon 2 of the CDKN2A gene, results from a C to A substitution at nucleotide position 170. The alanine at codon 57 is replaced by aspartic acid, an amino acid with dissimilar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This alteration has also been reported in a cohort of patients with Lynch syndrome-associated tumors and a personal or family history of sarcoma (de Angelis de Carvalho N et al. Cancers (Basel), 2020 Jul;12:). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Melanoma and neural system tumor syndrome Uncertain:1
Feb 21, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Oct 18, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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 an individual with endometrial sarcoma, tubular adenocarcinoma, and thyroid tumor (de Angelis de Carvalho et al., 2020); This variant is associated with the following publications: (PMID: 29641532, 32659967, 35029067) -

Melanoma, cutaneous malignant, susceptibility to, 2 Uncertain:1
Jul 02, 2018
Mendelics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Familial melanoma Uncertain:1
Dec 29, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 57 of the CDKN2A (p16INK4a) protein (p.Ala57Asp). This variant is present in population databases (rs372266620, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. ClinVar contains an entry for this variant (Variation ID: 483325). 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 tolerated. 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
Uncertain
0.44
BayesDel_addAF
Benign
-0.016
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
17
DANN
Uncertain
0.98
DEOGEN2
Benign
0.21
T;T;.;.;.;.;T;.
Eigen
Benign
-0.58
Eigen_PC
Benign
-0.72
FATHMM_MKL
Benign
0.50
N
LIST_S2
Benign
0.83
T;T;.;T;.;T;T;T
M_CAP
Uncertain
0.17
D
MetaRNN
Benign
0.28
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.69
T
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-2.2
N;.;.;N;.;.;.;.
REVEL
Uncertain
0.44
Sift
Benign
0.042
D;.;.;D;.;.;.;.
Sift4G
Benign
0.60
T;T;T;T;T;T;T;T
Polyphen
0.93
P;.;.;.;.;.;.;.
Vest4
0.36
MutPred
0.50
Loss of MoRF binding (P = 0.0448);Loss of MoRF binding (P = 0.0448);.;Loss of MoRF binding (P = 0.0448);.;.;.;.;
MVP
0.96
MPC
1.3
ClinPred
0.52
D
GERP RS
-1.0
Varity_R
0.48
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs372266620; hg19: chr9-21971188; API