chr5-176621218-G-T
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2
The NM_003085.5(SNCB):c.368C>A(p.Pro123His) variant causes a missense change. The variant allele was found at a frequency of 0.000281 in 1,612,146 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).
Frequency
Consequence
NM_003085.5 missense
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: 0.000204 AC: 31AN: 152154Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000169 AC: 42AN: 248540Hom.: 0 AF XY: 0.000164 AC XY: 22AN XY: 134428
GnomAD4 exome AF: 0.000289 AC: 422AN: 1459874Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 214AN XY: 726130
GnomAD4 genome AF: 0.000204 AC: 31AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74452
ClinVar
Submissions by phenotype
Lewy body dementia Pathogenic:2Other:1
The c.368C>A;p.(Pro123His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7026; OMIM: 602569.0002; PMID: 15365127) - PS4_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21045828) - PS3. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Synuclein) - PM1. The variant is present at low allele frequencies population databases (rs104893937 – gnomAD 0.002037%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
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Variant interpreted as Likely pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
SNCB-related disorder Pathogenic:1
The SNCB c.368C>A variant is predicted to result in the amino acid substitution p.Pro123His. This variant was reported in individuals with dementia with Lewy bodies (Ohtake et al. 2004. PubMed ID: 15365127, family study). A functional study showed that transgenic mice expressing this variant developed progressive neurodegeneration (Fujita et al. 2010. Pubmed ID: 21045828). Other studies elaborated on the mechanism of this variant (Janowska et al 2015. PubMed ID: 26332674; Psol et al. 2021. PubMed ID: 33760043). However, family segregation study shows that this variant does not produce a disease phenotype in all individuals suggesting reduced penetrance for this variant (Ohtake et al. 2004. PubMed ID: 15365127). This variant is reported in 0.036% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
not provided Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at