19-49168682-C-T
Variant summary
Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_017636.4(TRPM4):c.742C>T(p.Arg248Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000621 in 1,611,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. R248H) has been classified as Likely benign.
Frequency
Consequence
NM_017636.4 missense
Scores
Clinical Significance
Conservation
Publications
- erythrokeratodermia variabilis et progressiva 6Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
- progressive familial heart block type IBInheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
- erythrokeratodermia variabilisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- progressive familial heart blockInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Brugada syndromeInheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Genomics England PanelApp, ClinGen
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ACMG classification
Our verdict: Benign. The variant received -9 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000132 AC: 20AN: 151992Hom.: 0 Cov.: 30 show subpopulations
GnomAD2 exomes AF: 0.0000902 AC: 22AN: 243780 AF XY: 0.000121 show subpopulations
GnomAD4 exome AF: 0.0000548 AC: 80AN: 1459160Hom.: 0 Cov.: 33 AF XY: 0.0000551 AC XY: 40AN XY: 725742 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.000132 AC: 20AN: 151992Hom.: 0 Cov.: 30 AF XY: 0.000148 AC XY: 11AN XY: 74236 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Progressive familial heart block type IB Uncertain:1Benign:1
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. -
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Cardiovascular phenotype Uncertain:1
The p.R248C variant (also known as c.742C>T), located in coding exon 6 of the TRPM4 gene, results from a C to T substitution at nucleotide position 742. The arginine at codon 248 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with additional variants in other cardiac-related genes in a case of sudden unexpected death (Bagnall RD et al. Ann. Neurol., 2016 Apr;79:522-34). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
not specified Benign:1
Variant summary: TRPM4 c.742C>T (p.Arg248Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 243780 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 44 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRPM4 causing Progressive Familial Heart Block Type 1B phenotype (2.5e-06). c.742C>T has been reported in the literature in an individual affected with sudden unexpected death in epilepsy who also had VUSs in other genes (Bagnall_2016). This report does not provide unequivocal conclusions about association of the variant with Progressive Familial Heart Block Type 1B. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26704558). ClinVar contains an entry for this variant (Variation ID: 518807). Based on the evidence outlined above, the variant was classified as likely benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at