Genetic Variant TRPM2:p.Arg755Cys (chr21-44400313-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003307.4(TRPM2):c.2263C>T(p.Arg755Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 1,612,656 control chromosomes in the GnomAD database, including 2,430 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.041 ( 188 hom., cov: 33)

Exomes 𝑓: 0.052 ( 2242 hom. )

Consequence

TRPM2
NM_003307.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.113

Publications

13 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003799945).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM2	NM_003307.4 link	c.2263C>T	p.Arg755Cys	missense_variant	Exon 15 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.2263C>T	p.Arg755Cys	missense_variant	Exon 15 of 32	1	NM_003307.4	ENSP00000381023.1		O94759-1

Frequencies

GnomAD3 genomes

AF:

0.0407

AC:

6198

AN:

152156

Hom.:

188

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00985

Gnomad AMI

AF:

0.0713

Gnomad AMR

AF:

0.0281

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0579

Gnomad OTH

AF:

0.0330

GnomAD2 exomes

AF:

0.0409

AC:

10192

AN:

249314

AF XY:

0.0416

show subpopulations

Gnomad AFR exome

AF:

0.00824

Gnomad AMR exome

AF:

0.0225

Gnomad ASJ exome

AF:

0.0296

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0928

Gnomad NFE exome

AF:

0.0549

Gnomad OTH exome

AF:

0.0441

GnomAD4 exome

AF:

0.0521

AC:

76037

AN:

1460382

Hom.:

2242

Cov.:

AF XY:

0.0515

AC XY:

37409

AN XY:

726484

show subpopulations

African (AFR)

AF:

0.00759

AC:

254

AN:

33476

American (AMR)

AF:

0.0234

AC:

1046

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.0299

AC:

781

AN:

26128

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39694

South Asian (SAS)

AF:

0.0196

AC:

1688

AN:

86192

European-Finnish (FIN)

AF:

0.0941

AC:

4924

AN:

52314

Middle Eastern (MID)

AF:

0.0201

AC:

116

AN:

5766

European-Non Finnish (NFE)

AF:

0.0582

AC:

64706

AN:

1111766

Other (OTH)

AF:

0.0417

AC:

2519

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

3816

7632

11447

15263

19079

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2368

4736

7104

9472

11840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0407

AC:

6198

AN:

152274

Hom.:

188

Cov.:

AF XY:

0.0409

AC XY:

3043

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00982

AC:

408

AN:

41548

American (AMR)

AF:

0.0280

AC:

429

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.0170

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.103

AC:

1093

AN:

10606

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0579

AC:

3937

AN:

68026

Other (OTH)

AF:

0.0326

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

306

611

917

1222

1528

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0519

Hom.:

490

Bravo

AF:

0.0331

TwinsUK

AF:

0.0545

AC:

202

ALSPAC

AF:

0.0631

AC:

243

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.0548

AC:

471

ExAC

AF:

0.0404

AC:

4898

Asia WGS

AF:

0.00808

AC:

AN:

3478

EpiCase

AF:

0.0522

EpiControl

AF:

0.0507

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;D;.;.

Eigen

Benign

-0.14

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.39

LIST_S2

Uncertain

0.95

.;D;D;D

MetaRNN

Benign

0.0038

T;T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Pathogenic

3.1

M;M;.;.

PhyloP100

0.11

PrimateAI

Benign

0.40

PROVEAN

Pathogenic

-5.8

D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.68

MPC

0.69

ClinPred

0.055

GERP RS

1.7

Varity_R

0.63

gMVP

0.57

Mutation Taster

=90/10

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over