chr19-49168695-G-A

Position:

chr19-49168695-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017636.4(TRPM4):c.755G>A(p.Arg252His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0055 in 1,608,374 control chromosomes in the GnomAD database, including 29 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 0.0042 ( 1 hom., cov: 30)

Exomes 𝑓: 0.0056 ( 28 hom. )

Consequence

TRPM4
NM_017636.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.417

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0078031123).

BP6

Variant 19-49168695-G-A is Benign according to our data. Variant chr19-49168695-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241182.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=5, Uncertain_significance=1}. Variant chr19-49168695-G-A is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 633 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4 linkuse as main transcript	c.755G>A	p.Arg252His	missense_variant	6/25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10 linkuse as main transcript	c.755G>A	p.Arg252His	missense_variant	6/25	1	NM_017636.4	ENSP00000252826	P1	Q8TD43-1

Frequencies

GnomAD3 genomes

AF:

0.00417

AC:

633

AN:

151962

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00126

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00263

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0110

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00554

Gnomad OTH

AF:

0.00336

GnomAD3 exomes

AF:

0.00422

AC:

1000

AN:

237220

Hom.:

AF XY:

0.00424

AC XY:

546

AN XY:

128698

show subpopulations

Gnomad AFR exome

AF:

0.00106

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.0111

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00875

Gnomad NFE exome

AF:

0.00592

Gnomad OTH exome

AF:

0.00520

GnomAD4 exome

AF:

0.00564

AC:

8207

AN:

1456412

Hom.:

Cov.:

AF XY:

0.00554

AC XY:

4011

AN XY:

724162

show subpopulations

Gnomad4 AFR exome

AF:

0.00135

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.0113

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000702

Gnomad4 FIN exome

AF:

0.00841

Gnomad4 NFE exome

AF:

0.00642

Gnomad4 OTH exome

AF:

0.00392

GnomAD4 genome

AF:

0.00417

AC:

633

AN:

151962

Hom.:

Cov.:

AF XY:

0.00472

AC XY:

350

AN XY:

74216

show subpopulations

Gnomad4 AFR

AF:

0.00126

Gnomad4 AMR

AF:

0.00263

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0110

Gnomad4 NFE

AF:

0.00554

Gnomad4 OTH

AF:

0.00336

Alfa

AF:

0.00585

Hom.:

Bravo

AF:

0.00361

TwinsUK

AF:

0.00782

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.000682

AC:

ESP6500EA

AF:

0.00628

AC:

ExAC

AF:

0.00378

AC:

458

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive familial heart block type IB

Uncertain:1Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	TRPM4: BP4, BS2 -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Apr 17, 2019

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2015

This alteration is classified as 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

0.073

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.36

T;D;.

Eigen

Benign

0.014

Eigen_PC

Benign

-0.15

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.85

T;T;T

MetaRNN

Benign

0.0078

T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.4

.;M;M

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.26

PROVEAN

Uncertain

-2.6

.;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0060

.;D;D

Sift4G

Uncertain

0.040

D;D;D

Polyphen

0.98, 0.99

.;D;D

Vest4

0.33, 0.34

MVP

0.86

MPC

0.41

ClinPred

0.018

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.45

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