Genetic Variant TRPM2:p.Gln1189Leu (chr21-44424868-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003307.4(TRPM2):c.3566A>T(p.Gln1189Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 29)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TRPM2
NM_003307.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.324

Publications

29 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:

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

TRPM2-AS links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05671683).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003307.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM2	NM_003307.4	MANE Select	c.3566A>T	p.Gln1189Leu	missense	Exon 24 of 32	NP_003298.2
TRPM2	NM_001320350.2		c.3716A>T	p.Gln1239Leu	missense	Exon 25 of 33	NP_001307279.2
TRPM2	NM_001433516.1		c.3566A>T	p.Gln1189Leu	missense	Exon 25 of 33	NP_001420445.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TRPM2	ENST00000397928.6	TSL:1 MANE Select	c.3566A>T	p.Gln1189Leu	missense	Exon 24 of 32	ENSP00000381023.1
TRPM2	ENST00000397932.6	TSL:1	c.3716A>T	p.Gln1239Leu	missense	Exon 25 of 33	ENSP00000381026.2
TRPM2	ENST00000300482.9	TSL:1	c.3566A>T	p.Gln1189Leu	missense	Exon 25 of 33	ENSP00000300482.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1452458

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721682

African (AFR)

AF:

0.00

AC:

AN:

33348

American (AMR)

AF:

0.00

AC:

AN:

43736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25890

East Asian (EAS)

AF:

0.00

AC:

AN:

39356

South Asian (SAS)

AF:

0.00

AC:

AN:

84628

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51792

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5128

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108618

Other (OTH)

AF:

0.00

AC:

AN:

59962

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

134193

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.27

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.20

M_CAP

Benign

0.046

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.69

PhyloP100

0.32

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.4

REVEL

Benign

0.0090

Sift

Benign

0.098

Sift4G

Benign

0.30

Polyphen

0.0

Vest4

0.20

MutPred

0.43

Loss of helix (P = 0.0196)

MVP

0.36

MPC

0.13

ClinPred

0.025

GERP RS

-1.3

Varity_R

0.079

gMVP

0.43

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over