NM_006073.4:c.1627C>A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_006073.4(TRDN):c.1627C>A(p.Gln543Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,500,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 1/1 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. Q543R) has been classified as Uncertain significance.
Frequency
Consequence
NM_006073.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 151964Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000217 AC: 26AN: 119792Hom.: 0 AF XY: 0.000202 AC XY: 13AN XY: 64352
GnomAD4 exome AF: 0.0000312 AC: 42AN: 1348144Hom.: 0 Cov.: 27 AF XY: 0.0000316 AC XY: 21AN XY: 664984
GnomAD4 genome AF: 0.000158 AC: 24AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13AN XY: 74336
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1;C3809536:Catecholaminergic polymorphic ventricular tachycardia 5 Uncertain:1
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not provided Uncertain:1
Has been reported in the compound heterozygous state in an individual who also carried a chromosome 22 microdeletion (PMID: 32703023); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32703023) -
not specified Benign:1
BS1, BP4 -
Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1
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Cardiovascular phenotype Benign:1
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