rs146564314

Positions:

• chr19-49168695-G-A
• chr19-49168695-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R252C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0056 (28 hom.)
• Consequence: TRPM4 NM_017636.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.417

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]

ACMG classification

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	UniProt
TRPM4	NM_017636.4	c.755G>A	p.Arg252His	missense_variant	6/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10	c.755G>A	p.Arg252His	missense_variant	6/25	1	NM_017636.4	P1

Frequencies

GnomAD3 genomes AF: 0.00417 AC: 633 AN: 151962 Hom.: 1 Cov.: 30

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.: 5 AF XY: 0.00424 AC XY: 546 AN XY: 128698

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.: 28 Cov.: 33 AF XY: 0.00554 AC XY: 4011 AN XY: 724162

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.: 1 Cov.: 30 AF XY: 0.00472 AC XY: 350 AN XY: 74216

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.: 8

Bravo AF: 0.00361

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00378 AC: 458

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Progressive familial heart block type IB Uncertain:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

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

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

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	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T;D;.
Eigen	Benign	0.014
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.85	T;T;T
MetaRNN	Benign	0.0078	T;T;T
MetaSVM	Benign	-0.81	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs146564314; hg19: chr19-49671952; COSMIC: COSV53267723; COSMIC: COSV53267723;