rs172155862

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017636.4(TRPM4):c.2561A>G(p.Gln854Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,577,780 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q854E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00077 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 4 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: -0.148

Publications

15 publications found

Variant links:

Genes affected

TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]

TRPM4 Gene-Disease associations (from GenCC):

erythrokeratodermia variabilis et progressiva 6
Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
progressive familial heart block type IB
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
erythrokeratodermia variabilis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
progressive familial heart block
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Brugada syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen

TRPM4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010563403).

BP6

Variant 19-49196790-A-G is Benign according to our data. Variant chr19-49196790-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 381691.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS2

High AC in GnomAd4 at 117 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4 link	c.2561A>G	p.Gln854Arg	missense_variant	Exon 17 of 25	ENST00000252826.10	NP_060106.2	Q8TD43-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 link	c.2561A>G	p.Gln854Arg	missense_variant	Exon 17 of 25	1	NM_017636.4	ENSP00000252826.4		Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.000769

AC:

117

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000806

AC:

159

AN:

197334

AF XY:

0.000883

show subpopulations

Gnomad AFR exome

AF:

0.0000875

Gnomad AMR exome

AF:

0.000643

Gnomad ASJ exome

AF:

0.00186

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.000384

GnomAD4 exome

AF:

0.00105

AC:

1493

AN:

1425508

Hom.:

Cov.:

AF XY:

0.00106

AC XY:

748

AN XY:

707902

show subpopulations

African (AFR)

AF:

0.000214

AC:

AN:

32766

American (AMR)

AF:

0.000788

AC:

AN:

41890

Ashkenazi Jewish (ASJ)

AF:

0.00242

AC:

AN:

25670

East Asian (EAS)

AF:

0.00

AC:

AN:

38040

South Asian (SAS)

AF:

0.00103

AC:

AN:

82614

European-Finnish (FIN)

AF:

0.000132

AC:

AN:

37928

Middle Eastern (MID)

AF:

0.00108

AC:

AN:

5580

European-Non Finnish (NFE)

AF:

0.00113

AC:

1248

AN:

1101692

Other (OTH)

AF:

0.000792

AC:

AN:

59328

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

186

280

373

466

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000768

AC:

117

AN:

152272

Hom.:

Cov.:

AF XY:

0.000792

AC XY:

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

41568

American (AMR)

AF:

0.00144

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.000865

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00117

AC:

ExAC

AF:

0.000707

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive familial heart block type IB

Uncertain:1Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 31, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified

Benign:1

Dec 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

TRPM4-related disorder

Benign:1

Feb 04, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Aug 26, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27711072, 23382873, 21887725, 24721656, 26820365, 29568272, 30821013, 30142439) -

Long QT syndrome

Benign:1

Jan 08, 2024

Dept of Medical Biology, Uskudar University

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

Criteria: BS1, BP4 -

Cardiovascular phenotype

Benign:1

Dec 21, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.1

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.49

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.0068

LIST_S2

Benign

0.53

M_CAP

Benign

0.041

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

PhyloP100

-0.15

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.45

REVEL

Benign

0.019

Sift

Benign

0.10

Sift4G

Benign

0.27

Polyphen

0.0080

Vest4

0.030

MVP

0.65

MPC

0.31

ClinPred

0.0011

GERP RS

0.15

Varity_R

0.13

gMVP

0.21

Mutation Taster

=85/15

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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rs172155862

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over