rs747809412

Variant names:

• chr4-52033589-T-A
• rs747809412
• NM_000232.5:c.85A>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM3_Strong PM2_Supporting PVS1_Moderate PP4_Strong

This summary comes from the ClinGen Evidence Repository: The NM_000232.5: c.85A>T p.(Arg29Ter) variant in SGCB is a nonsense variant that may cause loss of function of the protein. However, the premature stop encoded by this variant occurs within the first 100 base pairs, and the resulting transcript may escape nonsense mediated decay. The next in-frame methionine is at amino acid 100, and non-truncating variants upstream of this alternative start site are classified as likely pathogenic or pathogenic (c.265G>A p.(Val89Met), c.271C>T p.(Arg91Cys)) (PVS1_Moderate). This variant has been detected in at least five individuals with signs of limb girdle muscular dystrophy (PMID:11369190, 17994539, 25862795), including confirmed in trans with a likely pathogenic or pathogenic variant (c.377_384dup p.(Gly128GlnfsTer2), 1.0 pt; c.271C>T p.(Arg91Cys), 1.0 pt; PMID:17994539, 25862795, 11369190) (PM3_Strong). At least one patient with this variant showed progressive limb girdle muscle weakness and absent or severely reduced expression of β-sarcoglycan protein in skeletal muscle, which is highly specific for SGCB-related LGMD (PP4_Strong; PMID:25862795). The highest minor allele frequency of this variant is 0.00001758 in the European (non-Finnish) population in gnomAD v2.1.1 (2/113756 exome chromosomes), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1_Moderate, PM3_Strong, PP4_Strong, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA2918507/MONDO:0015152/184

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: SGCB NM_000232.5 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 1.88

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 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM3: For more information check the summary or visit ClinGen Evidence Repository.
• PP4: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5	c.85A>T	p.Arg29*	stop_gained	Exon 2 of 6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.34-3726A>T		intron_variant	Intron 1 of 4		XP_047272030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.85A>T	p.Arg29*	stop_gained	Exon 2 of 6	1	NM_000232.5	ENSP00000370839.6
SGCB	ENST00000506357.5	n.70A>T		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000421235.1
SGCB	ENST00000514133.1	n.52A>T		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000425818.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251468 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135910

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461698 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727178

Gnomad4 AFR exome AF: 0.00

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy Pathogenic:1

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000232.5: c.85A>T p.(Arg29Ter) variant in SGCB is a nonsense variant that may cause loss of function of the protein. However, the premature stop encoded by this variant occurs within the first 100 base pairs, and the resulting transcript may escape nonsense mediated decay. The next in-frame methionine is at amino acid 100, and non-truncating variants upstream of this alternative start site are classified as likely pathogenic or pathogenic (c.265G>A p.(Val89Met), c.271C>T p.(Arg91Cys)) (PVS1_Moderate). This variant has been detected in at least five individuals with signs of limb girdle muscular dystrophy (PMID: 11369190, 17994539, 25862795), including confirmed in trans with a likely pathogenic or pathogenic variant (c.377_384dup p.(Gly128GlnfsTer2), 1.0 pt; c.271C>T p.(Arg91Cys), 1.0 pt; PMID: 17994539, 25862795, 11369190) (PM3_Strong). At least one patient with this variant showed progressive limb girdle muscle weakness and absent or severely reduced expression of β-sarcoglycan protein in skeletal muscle, which is highly specific for SGCB-related LGMD (PP4_Strong; PMID: 25862795). The highest minor allele frequency of this variant is 0.00001758 in the European (non-Finnish) population in gnomAD v2.1.1 (2/113756 exome chromosomes), which is lower than the LGMD VCEP threshold (<0.00009) for PM2_Supporting, meeting this criterion (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): PVS1_Moderate, PM3_Strong, PP4_Strong, PM2_Supporting. -

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:1

Apr 12, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Benign	0.061
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.84	D
Vest4		0.86
GERP RS		-0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs747809412; hg19: chr4-52899755;