chr19-49200394-A-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_017636.4(TRPM4):c.2740A>T(p.Lys914Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,920 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017636.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPM4 | NM_017636.4 | c.2740A>T | p.Lys914Ter | stop_gained | 18/25 | ENST00000252826.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPM4 | ENST00000252826.10 | c.2740A>T | p.Lys914Ter | stop_gained | 18/25 | 1 | NM_017636.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000875 AC: 133AN: 151924Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00123 AC: 308AN: 251286Hom.: 0 AF XY: 0.00118 AC XY: 160AN XY: 135856
GnomAD4 exome AF: 0.00103 AC: 1511AN: 1461878Hom.: 1 Cov.: 33 AF XY: 0.00103 AC XY: 750AN XY: 727238
GnomAD4 genome AF: 0.000875 AC: 133AN: 152042Hom.: 0 Cov.: 31 AF XY: 0.000619 AC XY: 46AN XY: 74322
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 03, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 07, 2023 | Reported in both patients with Brugada syndrome and control subjects as well as in a cohort of stillbirth cases (PMID: 23382873, 25467552, 27711072, 30847666, 30615648); Published functional studies demonstrated p.(K914*) resulted in decreased expression of the TRPM4 channel, though a dominant effect was not established because the combined expression of wild-type and mutant TRPM4 channels was not studied (PMID: 23382873); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene or region of a gene for which loss of function is not a well-established mechanism of disease; This variant is associated with the following publications: (PMID: 30142439, no PMID, 24721656, 22750058, 27711072, 23382873, 30821013, 31345219, 30847666, 36982932, 37128952, 25467552, 30615648) - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | TRPM4: BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Apr 03, 2020 | - - |
TRPM4-related disorder Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 05, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | The c.2740A>T (p.Lys914Ter) variant is a stop gained variant that has been reported in at least two studies in which it is found in a heterozygous state in a total of four patients with Brugada syndrome (Liu et al. 2012; Hertz et al. 2015). The p.Lys914Ter variant was reported in two of 1914 controls (Liu et al. 2012) and is reported at a frequency of 0.00221 in the European (Non-Finnish) population of the Exome Aggregation Consortium. There is limited evidence linking the TRPM4 gene to Brugada syndrome. Functional analysis of the p.Lys914Ter variant protein in HEK-293 cells demonstrated the variant resulted in decreased total expression, a truncated protein and a lack of current in a single channel conductance test (Liu et al. 2012). Due to the potential impact of stop-gained variants and the evidence from the literature, the p.Lys914Ter variant is classified as a variant of unknown significance but suspicious for pathogenicity for TRPM4-related disorders. - |
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 10, 2019 | - - |
Progressive familial heart block type IB Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 24, 2019 | 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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at