19-49168301-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3PP5BS2

The NM_017636.4(TRPM4):c.490C>T(p.Arg164Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,830 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R164Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 0.346

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: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.81

PP5

Variant 19-49168301-C-T is Pathogenic according to our data. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488. Variant chr19-49168301-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 35488.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPM4	NM_017636.4 link	c.490C>T	p.Arg164Trp	missense_variant	Exon 5 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.490C>T	p.Arg164Trp	missense_variant	Exon 5 of 25	1	NM_017636.4	ENSP00000252826.4		Q8TD43-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

251426

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000547

AC:

AN:

1461830

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00000499

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive familial heart block type IB

Pathogenic:2

Aug 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Oct 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 164 of the TRPM4 protein (p.Arg164Trp). This variant is present in population databases (rs387907216, gnomAD 0.01%). This missense change has been observed in individual(s) with cardiac conduction disease (PMID: 20562447). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35488). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. Experimental studies have shown that this missense change affects TRPM4 function (PMID: 20562447). For these reasons, this variant has been classified as Pathogenic. -

Cardiovascular phenotype

Uncertain:1

Jun 03, 2021

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R164W variant (also known as c.490C>T), located in coding exon 5 of the TRPM4 gene, results from a C to T substitution at nucleotide position 490. The arginine at codon 164 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been described to segregate with variable presentations of heart block in one family, and was suggested to affect channel activity in in vitro studies (Liu H et al. Circ Cardiovasc Genet, 2010 Aug;3:374-85). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Uncertain

0.0

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

D;.

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.097

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.81

D;D

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.6

M;M

PhyloP100

0.35

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Benign

0.25

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.87

MutPred

0.59

Loss of methylation at R164 (P = 0.0432);Loss of methylation at R164 (P = 0.0432);

MVP

0.88

MPC

0.44

ClinPred

0.93

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.61

gMVP

0.77

Mutation Taster

=10/90

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over