chr19-49200328-C-T

Position:

chr19-49200328-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS2

The NM_017636.4(TRPM4):c.2674C>T(p.Arg892Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000859 in 1,613,968 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00090 ( 1 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 5.52

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 links:

TRPM4 (HGNC:):

TRPM4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 6: BayesDel_noAF, Cadd, Dann, MutationAssessor, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.11370331).

BP6

Variant 19-49200328-C-T is Benign according to our data. Variant chr19-49200328-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329866.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, Benign=1}. Variant chr19-49200328-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 70 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4 linkuse as main transcript	c.2674C>T	p.Arg892Cys	missense_variant	18/25	ENST00000252826.10	NP_060106.2	Q8TD43-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 linkuse as main transcript	c.2674C>T	p.Arg892Cys	missense_variant	18/25	1	NM_017636.4	ENSP00000252826.4		Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.000460

AC:

AN:

152086

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000597

AC:

150

AN:

251304

Hom.:

AF XY:

0.000560

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.00586

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000900

AC:

1316

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000887

AC XY:

645

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00551

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000966

Gnomad4 OTH exome

AF:

0.00132

GnomAD4 genome

AF:

0.000460

AC:

AN:

152086

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.000197

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000529

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000854

Hom.:

Bravo

AF:

0.000506

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000511

AC:

EpiCase

AF:

0.000927

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive familial heart block type IB

Uncertain:2Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jul 19, 2016	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2019

Identified in one individual with atrioventricular block who also harbors variants in the TNNI3K, SCN1B, and RYR2 genes in published literature (Daumy et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30142439, 26820365) -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 20, 2018

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

Uncertain

0.42

BayesDel_addAF

Uncertain

0.085

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.11

T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Pathogenic

3.4

M;.

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.2

D;D

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.69

MVP

0.91

MPC

1.2

ClinPred

0.65

GERP RS

4.2

Varity_R

0.94

gMVP

0.85

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over