NM_174934.4:c.617C>T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_174934.4(SCN4B):c.617C>T(p.Ser206Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_174934.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SCN4B | NM_174934.4 | c.617C>T | p.Ser206Leu | missense_variant | Exon 5 of 5 | ENST00000324727.9 | NP_777594.1 | |
SCN4B | NM_001142349.2 | c.287C>T | p.Ser96Leu | missense_variant | Exon 4 of 4 | NP_001135821.1 | ||
SCN4B | NM_001142348.2 | c.215C>T | p.Ser72Leu | missense_variant | Exon 3 of 3 | NP_001135820.1 | ||
SCN4B | NR_024527.2 | n.606C>T | non_coding_transcript_exon_variant | Exon 4 of 4 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251394Hom.: 0 AF XY: 0.0000957 AC XY: 13AN XY: 135870
GnomAD4 exome AF: 0.000160 AC: 234AN: 1461496Hom.: 0 Cov.: 31 AF XY: 0.000166 AC XY: 121AN XY: 727074
GnomAD4 genome AF: 0.0000920 AC: 14AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74358
ClinVar
Submissions by phenotype
Long QT syndrome 10 Uncertain:2
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This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 206 of the SCN4B protein (p.Ser206Leu). This variant is present in population databases (rs140348243, gnomAD 0.01%). This missense change has been observed in individual(s) with sudden infant death and/or atrial fibrillation (PMID: 20226894, 30821358, 31043699). ClinVar contains an entry for this variant (Variation ID: 191380). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects SCN4B function (PMID: 20226894). 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. -
SUDDEN INFANT DEATH SYNDROME Uncertain:1
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not provided Uncertain:1
Reported in five-month-old male with sudden infant death syndrome (SIDS), and a 61-year-old male reported to have a QTc interval of 452 msec (PMID: 20226894, 23861362); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Functional studies performed in two different model expression systems show that p.(S206L) alters cardiac sodium channel function by accentuating the late sodium current (PMID: 20226894); Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868); This variant is associated with the following publications: (PMID: 23861362, 21215473, 21454796, 23304551, 23604097, 23465283, 31043699, 30821358, 34722422, 20226894) -
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