chr21-44354664-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003307.4(TRPM2):​c.182C>T​(p.Ser61Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000054 ( 0 hom. )

Consequence

TRPM2
NM_003307.4 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.14
Variant links:
Genes affected
TRPM2 (HGNC:12339): (transient receptor potential cation channel subfamily M member 2) The protein encoded by this gene forms a tetrameric cation channel that is permeable to calcium, sodium, and potassium and is regulated by free intracellular ADP-ribose. The encoded protein is activated by oxidative stress and confers susceptibility to cell death. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. Additional transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2016]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.303889).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRPM2NM_003307.4 linkuse as main transcriptc.182C>T p.Ser61Leu missense_variant 2/32 ENST00000397928.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TRPM2ENST00000397928.6 linkuse as main transcriptc.182C>T p.Ser61Leu missense_variant 2/321 NM_003307.4 P1O94759-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152174
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000358
AC:
9
AN:
251486
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.0000615
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:
0.0000462
Gnomad NFE exome
AF:
0.0000615
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000540
AC:
79
AN:
1461852
Hom.:
0
Cov.:
30
AF XY:
0.0000481
AC XY:
35
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:
0.0000374
Gnomad4 NFE exome
AF:
0.0000647
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152174
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74336
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000135
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000659
AC:
8
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

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 GeneticsNov 21, 2022The c.182C>T (p.S61L) alteration is located in exon 2 (coding exon 2) of the TRPM2 gene. This alteration results from a C to T substitution at nucleotide position 182, causing the serine (S) at amino acid position 61 to be replaced by a leucine (L). 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
Benign
0.078
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.47
T;T;T;.;.
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.44
N
LIST_S2
Uncertain
0.87
.;D;D;D;T
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.30
T;T;T;T;T
MetaSVM
Benign
-0.70
T
MutationAssessor
Pathogenic
2.9
M;.;M;.;M
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-3.5
D;D;D;D;D
REVEL
Benign
0.19
Sift
Uncertain
0.011
D;D;D;D;D
Sift4G
Benign
0.11
T;D;T;T;T
Polyphen
0.32
B;.;B;P;.
Vest4
0.43
MVP
0.50
MPC
0.40
ClinPred
0.93
D
GERP RS
4.8
Varity_R
0.34
gMVP
0.56

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200293453; hg19: chr21-45774547; COSMIC: COSV55968116; API