rs747809412

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_SupportingPM3_StrongPP4_StrongPVS1_Moderate

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

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:2

Conservation

PhyloP100: 1.88

Publications

1 publications found

Variant links:

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

SGCB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 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 link	c.85A>T	p.Arg29*	stop_gained	Exon 2 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0
SGCB	NM_001440520.1 link	c.-323A>T		5_prime_UTR_variant	Exon 2 of 7		NP_001427449.1
SGCB	NM_001440519.1 link	c.34-3726A>T		intron_variant	Intron 1 of 4		NP_001427448.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SGCB	ENST00000381431.10 link	c.85A>T	p.Arg29*	stop_gained	Exon 2 of 6	1	NM_000232.5	ENSP00000370839.6	Q16585-1
SGCB	ENST00000506357.5 link	n.70A>T		non_coding_transcript_exon_variant	Exon 2 of 5	5		ENSP00000421235.1	H0Y8J3
SGCB	ENST00000514133.1 link	n.52A>T		non_coding_transcript_exon_variant	Exon 1 of 4	5		ENSP00000425818.1	H0YA15

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00000795

AC:

AN:

251468

AF XY:

0.00000736

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727178

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41436

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: reviewed by expert panel

LINK: link

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:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.61

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.061

Eigen_PC

Benign

-0.21

FATHMM_MKL

Uncertain

0.84

PhyloP100

1.9

Vest4

0.86

GERP RS

-0.69

Mutation Taster

=13/187

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over