rs172149856

chr19-49188641-G-Achr19-49188641-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_017636.4(TRPM4):c.1744G>A(p.Gly582Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000374 in 1,614,184 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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. G582C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00051 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (6 hom.)
• Consequence: TRPM4 NM_017636.4 missense, splice_region
• Scores: Splicing: ADA: 0.06886
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:8 B:3
• Conservation: PhyloP100: 4.47

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.122550696).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00036 (526/1461888) while in subpopulation MID AF= 0.0187 (108/5768). AF 95% confidence interval is 0.0159. There are 6 homozygotes in gnomad4_exome. There are 281 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPM4	NM_017636.4	c.1744G>A	p.Gly582Ser	missense_variant, splice_region_variant	13/25	ENST00000252826.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPM4	ENST00000252826.10	c.1744G>A	p.Gly582Ser	missense_variant, splice_region_variant	13/25	1	NM_017636.4	P1

Frequencies

GnomAD3 genomes AF: 0.000526 AC: 80 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000509 AC: 128 AN: 251470 Hom.: 0 AF XY: 0.000544 AC XY: 74 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000545

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.000360 AC: 526 AN: 1461888 Hom.: 6 Cov.: 34 AF XY: 0.000386 AC XY: 281 AN XY: 727246

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000212

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74480

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000498 Hom.: 1

Bravo AF: 0.000669

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000527 AC: 64

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 17, 2022	The p.Gly582Ser variant (rs172149856) has been previously reported in a cardiac conductive block patient who also carried the p.Ala432Thr variant but this variant has not been reported alone (Stallmeyer et al 2012). This variant is listed in the NHLBI GO Exome Sequencing Project with an overall population frequency of 0.07 percent and is listed in the Exome Aggregation Consortium Browser with an overall population frequency of 0.05 percent. The glycine at position 582 is moderately conserved (considering 15 species, Alamut v2.7.1) and computational analyses of the effects of the p.Gly582Ser variant on protein structure and function predict this variant to be benign (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Because the p.Gly582Ser variant has not been observed without the p.Ala432Thr variant there is not enough evidence to classify this variant with certainty. Pathogenic variants of TRPM4 are inherited in an autosomal dominant manner and are associated with progressive familial heart block, type IB (MIM: 604599). -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 31, 2020	This variant is associated with the following publications: (PMID: 21887725, 22750058, 26350513, 23382873, 27884173, 27207958, 28341588, 26820365) -

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

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Nov 07, 2017	- -
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. -

Brugada syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Blueprint Genetics

May 21, 2015

- -

Progressive familial heart block, type 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2018

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	0.14
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	19
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.047
Eigen_PC	Benign	0.022
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.87	N;N;N
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.92	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.54	T;T
Sift4G	Benign	0.20	T;T
Polyphen		0.031	B;B
Vest4		0.74
MVP		0.85
MPC		0.32
ClinPred		0.021	T
GERP RS		3.3
Varity_R		0.13
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.069
dbscSNV1_RF	Benign	0.29
SpliceAI score (max)		0.010		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: rs172149856; hg19: chr19-49691898;