1-50970485-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_078626.3(CDKN2C):​c.117G>T​(p.Arg39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,032 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CDKN2C
NM_078626.3 missense

Scores

6
9
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.08
Variant links:
Genes affected
CDKN2C (HGNC:1789): (cyclin dependent kinase inhibitor 2C) The protein encoded by this gene is a member of the INK4 family of cyclin-dependent kinase inhibitors. This protein has been shown to interact with CDK4 or CDK6, and prevent the activation of the CDK kinases, thus function as a cell growth regulator that controls cell cycle G1 progression. Ectopic expression of this gene was shown to suppress the growth of human cells in a manner that appears to correlate with the presence of a wild-type RB1 function. Studies in the knockout mice suggested the roles of this gene in regulating spermatogenesis, as well as in suppressing tumorigenesis. Two alternatively spliced transcript variants of this gene, which encode an identical protein, have been reported. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.841

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDKN2CNM_078626.3 linkuse as main transcriptc.117G>T p.Arg39Ser missense_variant 1/2 ENST00000371761.4 NP_523240.1
CDKN2CNM_001262.3 linkuse as main transcriptc.117G>T p.Arg39Ser missense_variant 2/3 NP_001253.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDKN2CENST00000371761.4 linkuse as main transcriptc.117G>T p.Arg39Ser missense_variant 1/21 NM_078626.3 ENSP00000360826 P1
CDKN2CENST00000396148.2 linkuse as main transcriptc.117G>T p.Arg39Ser missense_variant 2/31 ENSP00000379452 P1
CDKN2CENST00000262662.5 linkuse as main transcriptc.117G>T p.Arg39Ser missense_variant 3/42 ENSP00000262662 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461860
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727228
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:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152172
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74334
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 11, 2023The c.117G>T (p.R39S) alteration is located in exon 2 (coding exon 1) of the CDKN2C gene. This alteration results from a G to T substitution at nucleotide position 117, causing the arginine (R) at amino acid position 39 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;T;T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.90
.;D;.
M_CAP
Benign
0.049
D
MetaRNN
Pathogenic
0.84
D;D;D
MetaSVM
Benign
-0.45
T
MutationAssessor
Uncertain
2.9
M;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-4.9
D;D;D
REVEL
Uncertain
0.51
Sift
Uncertain
0.0010
D;D;D
Sift4G
Uncertain
0.013
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.88
MutPred
0.70
Loss of MoRF binding (P = 0.007);Loss of MoRF binding (P = 0.007);Loss of MoRF binding (P = 0.007);
MVP
0.86
MPC
1.4
ClinPred
1.0
D
GERP RS
3.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.97
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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: rs1645374028; hg19: chr1-51436157; API