Variant chr21-44366884-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_003307.4(TRPM2):c.554G>A(p.Arg185Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000726 in 1,612,412 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00077 ( 1 hom. )

Consequence

TRPM2
NM_003307.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.15

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:

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=0.31229424).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM2	NM_003307.4 link	c.554G>A	p.Arg185Gln	missense_variant	4/32	ENST00000397928.6	NP_003298.2	O94759-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
TRPM2	ENST00000397928.6 link	c.554G>A	p.Arg185Gln	missense_variant	4/32	1	NM_003307.4	ENSP00000381023.1	O94759-1
TRPM2	ENST00000397932.6 link	c.554G>A	p.Arg185Gln	missense_variant	4/33	1		ENSP00000381026.2	E9PGK7
TRPM2	ENST00000300482.9 link	c.554G>A	p.Arg185Gln	missense_variant	5/33	1		ENSP00000300482.5	O94759-1
TRPM2	ENST00000300481.13 link	c.554G>A	p.Arg185Gln	missense_variant	4/32	1		ENSP00000300481.9	O94759-2

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.000515

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000308

AC:

AN:

249790

Hom.:

AF XY:

0.000385

AC XY:

AN XY:

135034

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000492

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000497

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000774

AC:

1131

AN:

1460326

Hom.:

Cov.:

AF XY:

0.000755

AC XY:

548

AN XY:

726232

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000511

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000943

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000263

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.000121

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:

0.000515

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000376

Hom.:

Bravo

AF:

0.000219

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000362

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000474

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 submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The c.554G>A (p.R185Q) alteration is located in exon 4 (coding exon 4) of the TRPM2 gene. This alteration results from a G to A substitution at nucleotide position 554, causing the arginine (R) at amino acid position 185 to be replaced by a glutamine (Q). 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

0.11

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.34

T;T;.;.

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.84

.;T;T;T

M_CAP

Benign

0.0099

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

2.9

M;M;.;M

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.9

N;N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.019

D;D;D;D

Sift4G

Benign

0.33

T;T;T;T

Polyphen

1.0

D;D;D;.

Vest4

0.58

MVP

0.42

MPC

0.57

ClinPred

0.25

GERP RS

4.4

Varity_R

0.28

gMVP

0.34

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.

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