Variant chr21-44424879-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_003307.4(TRPM2):c.3577T>C(p.Trp1193Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TRPM2
NM_003307.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.80

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM2	NM_003307.4 link	c.3577T>C	p.Trp1193Arg	missense_variant	24/32	ENST00000397928.6	NP_003298.2	O94759-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM2	ENST00000397928.6 link	c.3577T>C	p.Trp1193Arg	missense_variant	24/32	1	NM_003307.4	ENSP00000381023.1		O94759-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455746

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

723732

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Jan 24, 2023

The c.3577T>C (p.W1193R) alteration is located in exon 24 (coding exon 24) of the TRPM2 gene. This alteration results from a T to C substitution at nucleotide position 3577, causing the tryptophan (W) at amino acid position 1193 to be replaced by an arginine (R). 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

0.43

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.57

D;D;.;.

Eigen

Benign

0.063

Eigen_PC

Benign

-0.047

FATHMM_MKL

Benign

0.76

LIST_S2

Benign

0.62

.;T;T;T

M_CAP

Pathogenic

0.35

MetaRNN

Pathogenic

0.75

D;D;D;D

MetaSVM

Uncertain

-0.15

MutationAssessor

Uncertain

2.8

M;M;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-6.9

D;D;D;D

REVEL

Uncertain

0.36

Sift

Benign

0.080

T;T;D;T

Sift4G

Benign

0.12

T;T;D;T

Polyphen

1.0

D;D;P;.

Vest4

0.77

MutPred

0.46

.;.;Gain of disorder (P = 3e-04);.;

MVP

0.67

MPC

0.63

ClinPred

0.99

GERP RS

3.8

Varity_R

0.59

gMVP

0.71

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over