4-52038237-G-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000232.5(SGCB):c.-10_22dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG(p.Ala8fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000767 in 1,265,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000060 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000079 ( 0 hom. )
Consequence
SGCB
NM_000232.5 frameshift
NM_000232.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.09
Genes affected
SGCB (HGNC:10806): (sarcoglycan beta) This gene encodes a member of the sarcoglycan family. Sarcoglycans are transmembrane components in the dystrophin-glycoprotein complex which help stabilize the muscle fiber membranes and link the muscle cytoskeleton to the extracellular matrix. Mutations in this gene have been associated with limb-girdle muscular dystrophy.[provided by RefSeq, Oct 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 61 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-52038237-G-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC is Pathogenic according to our data. Variant chr4-52038237-G-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 466601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SGCB | NM_000232.5 | c.-10_22dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG | p.Ala8fs | frameshift_variant | 1/6 | ENST00000381431.10 | NP_000223.1 | |
SGCB | XM_047416074.1 | c.-10_22dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG | p.Ala8fs | frameshift_variant | 1/5 | XP_047272030.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SGCB | ENST00000381431.10 | c.-10_22dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG | p.Ala8fs | frameshift_variant | 1/6 | 1 | NM_000232.5 | ENSP00000370839.6 | ||
SGCB | ENST00000506357.5 | n.-25_7dupGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG | non_coding_transcript_exon_variant | 1/5 | 5 | ENSP00000421235.1 |
Frequencies
GnomAD3 genomes AF: 0.0000597 AC: 9AN: 150846Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.0000790 AC: 88AN: 1114230Hom.: 0 Cov.: 31 AF XY: 0.0000764 AC XY: 41AN XY: 536482
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GnomAD4 genome AF: 0.0000597 AC: 9AN: 150846Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 4AN XY: 73642
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 04, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 30, 2023 | This variant occurs in a non-coding region of the SGCB gene. It may leave the encoded amino acid sequence of the SGCB protein unchanged or may create a premature translational stop signal (p.Ala8Glyfs*22). This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 12746421, 25862795; Invitae). This variant is also known as c.-10_22dup (Non-coding), –22+10dup, and PTC+25aa. ClinVar contains an entry for this variant (Variation ID: 466601). Studies have shown that this variant alters SGCB gene expression (PMID: 25862795). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 04, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 03, 2024 | - - |
Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 01, 2021 | Variant summary: SGCB c.-10_22dup32 is located in the untranslated mRNA region upstream and the coding region including the initiation codon.The variant was absent in 37246 control chromosomes (gnomAD v2), however, it is found in 9/150846 controls in gnomAD v3. c.-10_22dup32 has been reported in the literature in multiple individuals affected with mild Limb-Girdle Muscular Dystrophy in homozygous state (Boito_2003, Semplicini_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. This variant is predicted to result in p.Ala8Glyfs*22 if the first initiation codon is utilized for translation. However, biochemical data of residual sarcoglycan expression in skeletal muscle and mild phenotype in variant carriers suggest that the second initiation codon in the mutant gene may also be utilized, which results in a normal protein (Semplicini_2015). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Although this variant has been found in mutliple patients, due to lack of functional evidence, the variant was classified as likely pathogenic. - |
not provided Uncertain:1
Uncertain significance, flagged submission | clinical testing | Eurofins Ntd Llc (ga) | Aug 21, 2015 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at