rs200038418

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_017636.4(TRPM4):c.2531G>A(p.Gly844Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,551,218 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 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. G844V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0014 ( 1 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:3O:1

Conservation

PhyloP100: 0.108

Publications

24 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=0.027328104).

BP6

Variant 19-49196760-G-A is Benign according to our data. Variant chr19-49196760-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35489.

BS2

High AC in GnomAd4 at 221 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4 link	c.2531G>A	p.Gly844Asp	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.2531G>A	p.Gly844Asp	missense_variant	Exon 17 of 25	1	NM_017636.4	ENSP00000252826.4		Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.00145

AC:

221

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00641

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00157

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00105

AC:

165

AN:

157302

AF XY:

0.00103

show subpopulations

Gnomad AFR exome

AF:

0.000364

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000543

Gnomad NFE exome

AF:

0.00168

Gnomad OTH exome

AF:

0.00245

GnomAD4 exome

AF:

0.00141

AC:

1979

AN:

1398898

Hom.:

Cov.:

AF XY:

0.00139

AC XY:

964

AN XY:

691898

show subpopulations

African (AFR)

AF:

0.000219

AC:

AN:

32012

American (AMR)

AF:

0.00176

AC:

AN:

37552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25248

East Asian (EAS)

AF:

0.00

AC:

AN:

36452

South Asian (SAS)

AF:

0.0000125

AC:

AN:

80148

European-Finnish (FIN)

AF:

0.000662

AC:

AN:

36250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5640

European-Non Finnish (NFE)

AF:

0.00164

AC:

1787

AN:

1087210

Other (OTH)

AF:

0.00161

AC:

AN:

58386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

122

245

367

490

612

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00145

AC:

221

AN:

152320

Hom.:

Cov.:

AF XY:

0.00154

AC XY:

115

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41574

American (AMR)

AF:

0.00641

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00157

AC:

107

AN:

68026

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000846

Hom.:

Bravo

AF:

0.00186

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00155

AC:

ExAC

AF:

0.000721

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:8Benign:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Feb 14, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 25, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24721656, 25441424, 25231975, 23382873, 26636822, 21887725, 22750058, 27207958, 27181684, 33381229, 30142439, 21173080, 28494446, 30847666, 35205305, 36352534, 28315637, 38467355, 37511555, 26820365, 20562447) -

Clinical Genetics, Academic Medical Center

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Progressive familial heart block type IB

Pathogenic:1Uncertain:1Benign:1Other:1

Jan 01, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 27, 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. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genomeconnect - The Bow Foundation (GNAO1)

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 07-05-2018 by The University of Oklahoma Health Sciences Center. GenomeConnect-GNAO1 assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Cardiovascular phenotype

Uncertain:2

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1_strong, PS3_mod, BS1 -

Jun 05, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G844D variant (also known as c.2531G>A), located in coding exon 17 of the TRPM4 gene, results from a G to A substitution at nucleotide position 2531. The glycine at codon 844 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been detected in conjunction with cardiac conduction defects and arrhythmia in a variety of individuals and has been shown to segregate with disease in one family, but it has also been reported in healthy individuals (Liu H et al. Circ Cardiovasc Genet. 2010;3(4):374-85; Stallmeyer B et al. Hum Mutat. 2012; 33(1):109-17; Liu H et al. PLoS ONE 2013; 8(1):e54131; Celestino-Soper PB et al. PLoS ONE. 2015;10(12):e0143588; Daumy X et al. Int J Cardiol. 2016;207:349-58; Syam N et al. J Am Heart Assoc. 2016;5:e001625; Hof T et al. BMC Med. Genet., 2017 03;18:31; Auricchio A et al. Europace. 2023 Feb;25(2):643-650). Functional studies suggest the potential for gain of function effects (Liu H et al. Circ Cardiovasc Genet. 2010 Aug;3(4):374-85). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Since supporting evidence is limited and conflicting at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Mar 30, 2024

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

Dec 20, 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). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.74

M_CAP

Benign

0.029

MetaRNN

Benign

0.027

MetaSVM

Benign

-0.86

MutationAssessor

Benign

1.4

PhyloP100

0.11

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.44

REVEL

Benign

0.19

Sift

Uncertain

0.010

Sift4G

Benign

0.13

Polyphen

0.92

Vest4

0.78

MVP

0.69

MPC

1.1

ClinPred

0.036

GERP RS

-1.6

Varity_R

0.12

gMVP

0.18

Mutation Taster

=8/92

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over