rs777047595
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_017636.4(TRPM4):c.2665delC(p.His889ThrfsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,613,962 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017636.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000125 AC: 19AN: 151962Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000135 AC: 34AN: 251264Hom.: 0 AF XY: 0.000155 AC XY: 21AN XY: 135816
GnomAD4 exome AF: 0.000168 AC: 246AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.000149 AC XY: 108AN XY: 727244
GnomAD4 genome AF: 0.000125 AC: 19AN: 152080Hom.: 0 Cov.: 31 AF XY: 0.0000673 AC XY: 5AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:2
Has not been previously published as pathogenic or benign to our knowledge; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is not a known mechanism of disease; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 422801; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 30847666) -
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Progressive familial heart block type IB;C5193144:Erythrokeratodermia variabilis et progressiva 6 Uncertain:1
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Long QT syndrome Uncertain:1
Criteria: PVS1_Moderate -
Progressive familial heart block type IB Uncertain:1
This sequence change creates a premature translational stop signal (p.His889Thrfs*35) in the TRPM4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRPM4 cause disease. This variant is present in population databases (rs777047595, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 30847666). ClinVar contains an entry for this variant (Variation ID: 422801). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
The c.2665delC variant, located in coding exon 18 of the TRPM4 gene, results from a deletion of one nucleotide at nucleotide position 2665, causing a translational frameshift with a predicted alternate stop codon (p.H889Tfs*35). This variant was detected in an arrhythmia genetic testing cohort; however, clinical details were limited (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309).This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TRPM4 has not been clearly established as a mechanism of disease. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at