rs1553940687

Positions:

• chr4-52033587-TCTCTC-T

Variant summary

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

The ENST00000381431.10(SGCB):​c.82_86del​(p.Glu28LysfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCB ENST00000381431.10 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.95

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 103 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-52033587-TCTCTC-T is Pathogenic according to our data. Variant chr4-52033587-TCTCTC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 466608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-52033587-TCTCTC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCB	NM_000232.5	c.82_86del	p.Glu28LysfsTer5	frameshift_variant	2/6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.34-3729_34-3725del		intron_variant			XP_047272030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.82_86del	p.Glu28LysfsTer5	frameshift_variant	2/6	1	NM_000232.5	ENSP00000370839	P1
SGCB	ENST00000506357.5	c.68_72del	p.Glu24LysfsTer5	frameshift_variant, NMD_transcript_variant	2/5	5		ENSP00000421235
SGCB	ENST00000514133.1	c.49_53del	p.Glu17LysfsTer5	frameshift_variant, NMD_transcript_variant	1/4	5		ENSP00000425818

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant c.82_86del (p.Glu28LysfsTer5) in SGCB gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Glu28LysfsTer5 variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant causes a frameshift starting with codon Glutamic Acid 28, changes this amino acid to Lysine residue, and creates a premature Stop codon at position 5 of the new reading frame, denoted p.Glu28LysfsTer5. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 28, 2017	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in SGCB are known to be pathogenic (PMID: 18285821). This sequence change deletes 5 nucleotides from exon 2 of the SGCB mRNA (c.82_86delGAGAG), causing a frameshift at codon 28. This creates a premature translational stop signal (p.Glu28Lysfs*5) and is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 10, 2024	Criteria applied: PVS1,PM2_SUP,PM3_SUP -

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: rs1553940687; hg19: chr4-52899753;