rs1553940963

chr4-52038237-G-GCCGCCGCCGCCGCTGCCGCCATCTTCCCGCGC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000232.5(SGCB):c.22_23insGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG(p.Ala8GlyfsTer22) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. A8A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000060 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: SGCB NM_000232.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• 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]

ACMG classification

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 116 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	UniProt
SGCB	NM_000232.5	c.22_23insGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala8GlyfsTer22	frameshift_variant	1/6	ENST00000381431.10
SGCB	XM_047416074.1	c.22_23insGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala8GlyfsTer16	frameshift_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCB	ENST00000381431.10	c.22_23insGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala8GlyfsTer22	frameshift_variant	1/6	1	NM_000232.5	P1
SGCB	ENST00000506357.5	c.8_9insGCGCGGGAAGATGGCGGCAGCGGCGGCGGCGG	p.Ala4GlyfsTer22	frameshift_variant, NMD_transcript_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.0000597 AC: 9 AN: 150846 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000741

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000790 AC: 88 AN: 1114230 Hom.: 0 Cov.: 31 AF XY: 0.0000764 AC XY: 41 AN XY: 536482

Gnomad4 AFR exome AF: 0.0000862

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000922

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000597 AC: 9 AN: 150846 Hom.: 0 Cov.: 32 AF XY: 0.0000543 AC XY: 4 AN XY: 73642

Gnomad4 AFR AF: 0.0000969

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000741

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 17, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	- -

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

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553940963; hg19: chr4-52904403;