chr21-44369195-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003307.4(TRPM2):ā€‹c.623G>Cā€‹(p.Gly208Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,611,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000033 ( 0 hom., cov: 33)
Exomes š‘“: 0.000038 ( 0 hom. )

Consequence

TRPM2
NM_003307.4 missense

Scores

1
12
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.58
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TRPM2NM_003307.4 linkuse as main transcriptc.623G>C p.Gly208Ala missense_variant 5/32 ENST00000397928.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TRPM2ENST00000397928.6 linkuse as main transcriptc.623G>C p.Gly208Ala missense_variant 5/321 NM_003307.4 P1O94759-1

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152142
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000574
AC:
14
AN:
243928
Hom.:
0
AF XY:
0.0000680
AC XY:
9
AN XY:
132408
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000176
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000334
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000547
Gnomad OTH exome
AF:
0.000170
GnomAD4 exome
AF:
0.0000377
AC:
55
AN:
1458926
Hom.:
0
Cov.:
33
AF XY:
0.0000358
AC XY:
26
AN XY:
725694
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000158
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000369
Gnomad4 OTH exome
AF:
0.0000996
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152142
Hom.:
0
Cov.:
33
AF XY:
0.0000404
AC XY:
3
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000824
AC:
10

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 GeneticsJun 09, 2022The c.623G>C (p.G208A) alteration is located in exon 5 (coding exon 5) of the TRPM2 gene. This alteration results from a G to C substitution at nucleotide position 623, causing the glycine (G) at amino acid position 208 to be replaced by an alanine (A). 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
Uncertain
0.39
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D;D;.;.
Eigen
Uncertain
0.54
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
.;D;D;D
M_CAP
Benign
0.033
D
MetaRNN
Uncertain
0.74
D;D;D;D
MetaSVM
Benign
-0.84
T
MutationAssessor
Uncertain
2.8
M;M;.;M
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Uncertain
0.69
T
PROVEAN
Uncertain
-4.0
D;D;D;D
REVEL
Uncertain
0.41
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Benign
0.080
T;T;T;D
Polyphen
1.0
D;D;D;.
Vest4
0.73
MVP
0.38
MPC
0.64
ClinPred
0.79
D
GERP RS
3.5
Varity_R
0.91
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs202197856; hg19: chr21-45789078; COSMIC: COSV55968252; COSMIC: COSV55968252; API