rs1060504181

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_058195.4(CDKN2A):​c.289G>T​(p.Ala97Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 in silico tools predict a benign 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. A97G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

CDKN2A
NM_058195.4 missense

Scores

4
13

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0300
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 Uncertain_significance. Variant got 4 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 13 benign, 17 uncertain in NM_058195.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-21971112-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376380.Status of the report is no_assertion_criteria_provided, 0 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.22056368).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDKN2ANM_058195.4 linkuse as main transcriptc.289G>T p.Ala97Ser missense_variant 2/3 ENST00000579755.2
CDKN2ANM_000077.5 linkuse as main transcriptc.246G>T p.Val82= synonymous_variant 2/3 ENST00000304494.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDKN2AENST00000579755.2 linkuse as main transcriptc.289G>T p.Ala97Ser missense_variant 2/31 NM_058195.4 Q8N726-1
CDKN2AENST00000304494.10 linkuse as main transcriptc.246G>T p.Val82= synonymous_variant 2/31 NM_000077.5 P2P42771-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1452018
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
722740
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.064
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
12
DANN
Benign
0.97
DEOGEN2
Benign
0.030
T;T
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.25
FATHMM_MKL
Benign
0.67
D
LIST_S2
Benign
0.42
.;T
M_CAP
Uncertain
0.22
D
MetaRNN
Benign
0.22
T;T
MetaSVM
Benign
-0.64
T
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;N;N;N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-2.2
.;N
REVEL
Uncertain
0.32
Sift
Benign
0.078
.;T
Sift4G
Benign
0.39
T;T
Vest4
0.18
MVP
0.87
ClinPred
0.20
T
GERP RS
3.0

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-21971112; COSMIC: COSV58698274; COSMIC: COSV58698274; API