chr4-52033587-TCTCTC-T

Variant names:

• chr4-52033587-TCTCTC-T
• rs1553940687
• NM_000232.5:c.82_86delGAGAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000232.5(SGCB):​c.82_86delGAGAG​(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 NM_000232.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.95
• Publications: 0 publications found

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]

SGCB Gene-Disease associations (from GenCC):

• autosomal recessive limb-girdle muscular dystrophy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2E

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 77 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 466608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000232.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	NM_000232.5	MANE Select	c.82_86delGAGAG	p.Glu28LysfsTer5	frameshift	Exon 2 of 6	NP_000223.1
	SGCB	NM_001440520.1		c.-326_-322delGAGAG		5_prime_UTR	Exon 2 of 7	NP_001427449.1
	SGCB	NM_001440519.1		c.34-3729_34-3725delGAGAG		intron	N/A	NP_001427448.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.82_86delGAGAG	p.Glu28LysfsTer5	frameshift	Exon 2 of 6	ENSP00000370839.6
	SGCB	ENST00000506357.5	TSL:5	n.67_71delGAGAG		non_coding_transcript_exon	Exon 2 of 5	ENSP00000421235.1
	SGCB	ENST00000514133.1	TSL:5	n.49_53delGAGAG		non_coding_transcript_exon	Exon 1 of 4	ENSP00000425818.1

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

Apr 10, 2024

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PM2_SUP,PM3_SUP

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Mar 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Glu28Lysfs*5) in the SGCB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCB are known to be pathogenic (PMID: 15938573, 18285821). This variant is not present in population databases (gnomAD no frequency). 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: 466608). For these reasons, this variant has been classified as Pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.9
Mutation Taster		=8/192	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1553940687; hg19: chr4-52899753;