rs756750256

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000077.5(CDKN2A):​c.197A>T​(p.His66Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. H66R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CDKN2A
NM_000077.5 missense

Scores

3
10
5

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.647
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 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000077.5
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CDKN2ANM_000077.5 linkuse as main transcriptc.197A>T p.His66Leu missense_variant 2/3 ENST00000304494.10
CDKN2ANM_058195.4 linkuse as main transcriptc.240A>T p.Pro80= synonymous_variant 2/3 ENST00000579755.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CDKN2AENST00000304494.10 linkuse as main transcriptc.197A>T p.His66Leu missense_variant 2/31 NM_000077.5 P2P42771-1
CDKN2AENST00000579755.2 linkuse as main transcriptc.240A>T p.Pro80= synonymous_variant 2/31 NM_058195.4 Q8N726-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Benign
22
DANN
Benign
0.97
DEOGEN2
Uncertain
0.55
D;T;.;.;.;.;T;.
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.77
T;T;.;T;.;T;T;T
M_CAP
Pathogenic
0.76
D
MetaRNN
Uncertain
0.61
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.49
D
MutationTaster
Benign
0.80
D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-6.2
D;.;.;D;.;.;.;.
REVEL
Uncertain
0.63
Sift
Benign
0.063
T;.;.;D;.;.;.;.
Sift4G
Benign
0.17
T;T;T;T;T;T;T;T
Polyphen
0.92
P;.;.;.;.;.;.;.
Vest4
0.31
MutPred
0.58
Loss of catalytic residue at G67 (P = 0.0652);Loss of catalytic residue at G67 (P = 0.0652);.;Loss of catalytic residue at G67 (P = 0.0652);.;.;.;.;
MVP
0.99
MPC
0.87
ClinPred
0.70
D
GERP RS
5.8
Varity_R
0.46
gMVP
0.82

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: chr9-21971161; COSMIC: COSV58702034; COSMIC: COSV58702034; API