chr9-21968234-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000077.5(CDKN2A):​c.466G>T​(p.Asp156Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDKN2A
NM_000077.5 missense

Scores

1
1
16

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: -0.864
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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;
BP4
Computational evidence support a benign effect (MetaRNN=0.15727243).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDKN2ANM_000077.5 linkuse as main transcriptc.466G>T p.Asp156Tyr missense_variant 3/3 ENST00000304494.10 NP_000068.1
CDKN2ANM_058195.4 linkuse as main transcriptc.*110G>T 3_prime_UTR_variant 3/3 ENST00000579755.2 NP_478102.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDKN2AENST00000304494.10 linkuse as main transcriptc.466G>T p.Asp156Tyr missense_variant 3/31 NM_000077.5 ENSP00000307101 P2P42771-1
CDKN2AENST00000579755.2 linkuse as main transcriptc.*110G>T 3_prime_UTR_variant 3/31 NM_058195.4 ENSP00000462950 Q8N726-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251264
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135834
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:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461722
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727172
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 10, 2023The p.D156Y variant (also known as c.466G>T), located in coding exon 3 of the CDKN2A gene, results from a G to T substitution at nucleotide position 466. The aspartic acid at codon 156 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 20, 2023This missense variant replaces aspartic acid with tyrosine at codon 156 of the CDKN2A (p16INK4A) protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDKN2A-related disorders in the literature. This variant has been identified in 1/251264 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. -
Familial melanoma Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 12, 2022Algorithms 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: "Deleterious"; PolyPhen-2: "Benign"; 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. ClinVar contains an entry for this variant (Variation ID: 1171898). This variant has not been reported in the literature in individuals affected with CDKN2A (p16INK4a)-related conditions. This variant is present in population databases (rs755445934, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 156 of the CDKN2A (p16INK4a) protein (p.Asp156Tyr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.076
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
12
DANN
Benign
0.81
DEOGEN2
Benign
0.11
T;.;.;.
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.99
FATHMM_MKL
Benign
0.17
N
LIST_S2
Benign
0.55
T;.;.;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.16
T;T;T;T
MetaSVM
Benign
-0.87
T
MutationTaster
Benign
1.0
N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.2
N;.;.;.
REVEL
Benign
0.20
Sift
Uncertain
0.0020
D;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;D
Polyphen
0.94
P;.;.;.
Vest4
0.17
MutPred
0.42
Gain of phosphorylation at D156 (P = 0.0081);.;.;.;
MVP
0.79
ClinPred
0.098
T
GERP RS
-2.3
Varity_R
0.16

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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: rs755445934; hg19: chr9-21968233; API