Variant chr21-44366874-A-G 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.544A>G(p.Met182Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,612,850 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TRPM2
NM_003307.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.85

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 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=0.2837302).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM2	NM_003307.4 linkuse as main transcript	c.544A>G	p.Met182Val	missense_variant	4/32	ENST00000397928.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM2	ENST00000397928.6 linkuse as main transcript	c.544A>G	p.Met182Val	missense_variant	4/32	1	NM_003307.4	P1	O94759-1
TRPM2	ENST00000397932.6 linkuse as main transcript	c.544A>G	p.Met182Val	missense_variant	4/33	1
TRPM2	ENST00000300482.9 linkuse as main transcript	c.544A>G	p.Met182Val	missense_variant	5/33	1		P1	O94759-1
TRPM2	ENST00000300481.13 linkuse as main transcript	c.544A>G	p.Met182Val	missense_variant	4/32	1			O94759-2

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461016

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726678

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:

0.00

Gnomad4 NFE exome

AF:

0.0000162

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151834

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74138

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

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

Jun 17, 2024

The c.544A>G (p.M182V) alteration is located in exon 4 (coding exon 4) of the TRPM2 gene. This alteration results from a A to G substitution at nucleotide position 544, causing the methionine (M) at amino acid position 182 to be replaced by a valine (V). 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

0.19

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

T;T;.;.

Eigen

Benign

0.077

Eigen_PC

Benign

0.074

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

.;T;T;T

M_CAP

Benign

0.0075

MetaRNN

Benign

0.28

T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.9

L;L;.;L

MutationTaster

Benign

0.99

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.8

N;N;N;N

REVEL

Benign

0.12

Sift

Uncertain

0.0090

D;D;D;D

Sift4G

Benign

0.091

T;T;T;D

Polyphen

0.86

P;P;P;.

Vest4

0.40

MutPred

0.58

Gain of methylation at K183 (P = 0.0238);Gain of methylation at K183 (P = 0.0238);Gain of methylation at K183 (P = 0.0238);Gain of methylation at K183 (P = 0.0238);

MVP

0.28

MPC

0.25

ClinPred

0.75

GERP RS

3.2

Varity_R

0.45

gMVP

0.50

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