rs113100797

Positions:

• chr19-49196501-TGCTGCGGGGGCC-T
• chr19-49196501-TGCTGCGGGGGCC-TGCTGCGGGGGCCGCTGCGGGGGCC

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The ENST00000252826.10(TRPM4):​c.2283_2294del​(p.Cys763_Arg766del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00711 in 1,556,054 control chromosomes in the GnomAD database, including 669 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C758C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.037 (339 hom., cov: 31)
  • Exomes 𝑓: 0.0038 (330 hom.)
• Consequence: TRPM4 ENST00000252826.10 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.36

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 -14 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000252826.10.
• BP6: Variant 19-49196501-TGCTGCGGGGGCC-T is Benign according to our data. Variant chr19-49196501-TGCTGCGGGGGCC-T is described in ClinVar as [Likely_benign]. Clinvar id is 415729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49196501-TGCTGCGGGGGCC-T is described in Lovd as [Benign]. Variant chr19-49196501-TGCTGCGGGGGCC-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPM4	NM_017636.4	c.2283_2294del	p.Cys763_Arg766del	inframe_deletion	17/25	ENST00000252826.10	NP_060106.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPM4	ENST00000252826.10	c.2283_2294del	p.Cys763_Arg766del	inframe_deletion	17/25	1	NM_017636.4	ENSP00000252826	P1

Frequencies

GnomAD3 genomes AF: 0.0369 AC: 5611 AN: 152062 Hom.: 327 Cov.: 31

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0321

GnomAD3 exomes AF: 0.00859 AC: 1356 AN: 157942 Hom.: 76 AF XY: 0.00673 AC XY: 577 AN XY: 85712

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.00841

Gnomad ASJ exome AF: 0.000357

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000382

Gnomad FIN exome AF: 0.0000940

Gnomad NFE exome AF: 0.000588

Gnomad OTH exome AF: 0.00633

GnomAD4 exome AF: 0.00384 AC: 5392 AN: 1403874 Hom.: 330 AF XY: 0.00325 AC XY: 2258 AN XY: 693886

Gnomad4 AFR exome AF: 0.130

Gnomad4 AMR exome AF: 0.00858

Gnomad4 ASJ exome AF: 0.0000795

Gnomad4 EAS exome AF: 0.0000272

Gnomad4 SAS exome AF: 0.000412

Gnomad4 FIN exome AF: 0.0000238

Gnomad4 NFE exome AF: 0.000214

Gnomad4 OTH exome AF: 0.0102

GnomAD4 genome AF: 0.0372 AC: 5664 AN: 152180 Hom.: 339 Cov.: 31 AF XY: 0.0365 AC XY: 2716 AN XY: 74414

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.00283 Hom.: 4

Bravo AF: 0.0426

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2016

- -

Progressive familial heart block type IB Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2016

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Restrictive cardiomyopathy;C0878544:Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs113100797; hg19: chr19-49699758;