rs138877636
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000232.5(SGCB):c.496A>G(p.Ile166Val) variant causes a missense change. The variant allele was found at a frequency of 0.000341 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. I166I) has been classified as Likely benign.
Frequency
Consequence
NM_000232.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCB | NM_000232.5 | c.496A>G | p.Ile166Val | missense_variant | 4/6 | ENST00000381431.10 | |
SGCB | XM_047416074.1 | c.286A>G | p.Ile96Val | missense_variant | 3/5 | ||
SGCB | XM_047416075.1 | c.199A>G | p.Ile67Val | missense_variant | 3/5 | ||
SGCB | XM_047416076.1 | c.199A>G | p.Ile67Val | missense_variant | 3/5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCB | ENST00000381431.10 | c.496A>G | p.Ile166Val | missense_variant | 4/6 | 1 | NM_000232.5 | P1 | |
SGCB | ENST00000506357.5 | c.*278A>G | 3_prime_UTR_variant, NMD_transcript_variant | 5/5 | 5 | ||||
SGCB | ENST00000514133.1 | c.*291A>G | 3_prime_UTR_variant, NMD_transcript_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000276 AC: 42AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000370 AC: 93AN: 251438Hom.: 0 AF XY: 0.000353 AC XY: 48AN XY: 135890
GnomAD4 exome AF: 0.000348 AC: 508AN: 1461528Hom.: 0 Cov.: 31 AF XY: 0.000338 AC XY: 246AN XY: 727100
GnomAD4 genome ? AF: 0.000276 AC: 42AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18AN XY: 74344
ClinVar
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2E Uncertain:4Other:1
not provided, no classification provided | phenotyping only | GenomeConnect - Invitae Patient Insights Network | - | Variant interpreted as Uncertain significance and reported on 04-21-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 21, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 10, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 24, 2022 | This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 166 of the SGCB protein (p.Ile166Val). This variant is present in population databases (rs138877636, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with SGCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 285961). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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 | Revvity Omics, Revvity | Jun 22, 2023 | - - |
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 25, 2023 | BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 10, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2018 | A variant of uncertain significance has been identified in the SGCB gene. The I166V variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The I166V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 10, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2022 | The c.496A>G (p.I166V) alteration is located in exon 4 (coding exon 4) of the SGCB gene. This alteration results from a A to G substitution at nucleotide position 496, causing the isoleucine (I) at amino acid position 166 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Qualitative or quantitative defects of beta-sarcoglycan Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at