Genetic Variant TRPM2:p.Ala1119Val (chr21-44418450-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_003307.4(TRPM2):c.3356C>T(p.Ala1119Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000731 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00077 ( 0 hom. )

Consequence

TRPM2
NM_003307.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.52

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]

TRPM2 links:

TRPM2-AS (HGNC:50758): (TRPM2 antisense RNA)

TRPM2-AS links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02047968).

BP6

Variant 21-44418450-C-T is Benign according to our data. Variant chr21-44418450-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3770637.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM2	NM_003307.4 link	c.3356C>T	p.Ala1119Val	missense_variant	Exon 22 of 32	ENST00000397928.6	NP_003298.2	O94759-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM2	ENST00000397928.6 link	c.3356C>T	p.Ala1119Val	missense_variant	Exon 22 of 32	1	NM_003307.4	ENSP00000381023.1		O94759-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000597

AC:

150

AN:

251198

Hom.:

AF XY:

0.000516

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00107

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000766

AC:

1119

AN:

1461720

Hom.:

Cov.:

AF XY:

0.000705

AC XY:

513

AN XY:

727152

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000336

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000394

Gnomad4 NFE exome

AF:

0.000923

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.000401

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000694

Hom.:

Bravo

AF:

0.000419

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000741

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00101

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TRPM2: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.34

T;T;.;.

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.72

.;T;T;T

M_CAP

Benign

0.032

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Uncertain

2.4

M;M;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.1

N;N;N;N

REVEL

Benign

0.081

Sift

Benign

0.14

T;T;T;T

Sift4G

Benign

0.27

T;T;T;T

Polyphen

0.12

B;B;P;.

Vest4

0.26

MVP

0.63

MPC

0.16

ClinPred

0.017

GERP RS

3.0

Varity_R

0.070

gMVP

0.27

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over