11-118166957-G-C
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_004588.5(SCN2B):c.578C>G(p.Thr193Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000218 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T193I) has been classified as Uncertain significance.
Frequency
Consequence
NM_004588.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN2B | NM_004588.5 | c.578C>G | p.Thr193Arg | missense_variant | 4/4 | ENST00000278947.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN2B | ENST00000278947.6 | c.578C>G | p.Thr193Arg | missense_variant | 4/4 | 1 | NM_004588.5 | P1 | |
SCN2B | ENST00000669850.1 | n.820C>G | non_coding_transcript_exon_variant | 4/4 | |||||
SCN2B | ENST00000658882.1 | c.*403C>G | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251462Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135908
GnomAD4 exome AF: 0.000232 AC: 339AN: 1461856Hom.: 0 Cov.: 31 AF XY: 0.000232 AC XY: 169AN XY: 727230
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74342
ClinVar
Submissions by phenotype
Atrial fibrillation, familial, 14 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 193 of the SCN2B protein (p.Thr193Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SCN2B-related conditions. ClinVar contains an entry for this variant (Variation ID: 408874). 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 tolerated. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 20, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2017 | A variant of uncertain significance has been identified in the SCN2B gene. The T193R variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed in 1/10,406 (0.01%) alleles from individuals of African ancestry, and in 4/66,736 (0.006%) alleles from individuals of Non-Finnish European ancestry in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T193R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2022 | 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