rs200761715

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP3BA1

This summary comes from the ClinGen Evidence Repository: The NM_000232.5: c.799C>T variant in SGCB is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 267 (p.Arg267Cys). The filtering allele frequency of this variant is 0.01396 in the South Asian population in gnomAD v2.1.1 (the lower threshold of the 95% CI of 462/30614 exome chromosomes), which is higher than the LGMD VCEP threshold (>0.002) for BA1 and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.75, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the predictive pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BA1, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA2918272/MONDO:0015152/184

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 28 hom. )

Consequence

SGCB
NM_000232.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:10

Conservation

PhyloP100: 7.90

Publications

4 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: Benign. The variant received -7 ACMG points.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

BA1

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.799C>T	p.Arg267Cys	missense_variant	Exon 6 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0
SGCB	NM_001440519.1 link	c.589C>T	p.Arg197Cys	missense_variant	Exon 5 of 5		NP_001427448.1
SGCB	NM_001440520.1 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 7 of 7		NP_001427449.1
SGCB	XM_047416076.1 link	c.502C>T	p.Arg168Cys	missense_variant	Exon 5 of 5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10 link	c.799C>T	p.Arg267Cys	missense_variant	Exon 6 of 6	1	NM_000232.5	ENSP00000370839.6		Q16585-1

Frequencies

GnomAD3 genomes

AF:

0.000565

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00203

AC:

511

AN:

251442

AF XY:

0.00269

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000237

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00107

AC:

1564

AN:

1461808

Hom.:

Cov.:

AF XY:

0.00150

AC XY:

1092

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.000268

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.000176

AC:

AN:

39696

South Asian (SAS)

AF:

0.0150

AC:

1298

AN:

86252

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00470

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000131

AC:

146

AN:

1111976

Other (OTH)

AF:

0.00118

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

177

266

354

443

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<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:

0.000552

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41558

American (AMR)

AF:

0.000392

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.0137

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000242

Hom.:

Bravo

AF:

0.000223

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00222

AC:

269

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.000327

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Benign:3

Sep 01, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 19, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Sep 23, 2016

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2E

Benign:3

Jan 11, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Limb-girdle muscular dystrophy, recessive

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy

Benign:1

Jan 09, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Benign

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000232.5: c.799C>T variant in SGCB is a missense variant predicted to cause substitution of arginine by cysteine at amino acid 267 (p.Arg267Cys). The filtering allele frequency of this variant is 0.01396 in the South Asian population in gnomAD v2.1.1 (the lower threshold of the 95% CI of 462/30614 exome chromosomes), which is higher than the LGMD VCEP threshold (>0.002) for BA1 and therefore meets this criterion (BA1). The computational predictor REVEL gives a score of 0.75, which exceeds the threshold of ≥0.70, evidence that correlates with impact to DYSF function (PP3). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive limb girdle muscular dystrophy. Although there are both pathogenic and benign types of evidence for this variant, the predictive pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/09/2025): BA1, PP3. -

Qualitative or quantitative defects of beta-sarcoglycan

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SGCB: BS1, BS2 -

Hypertrophic cardiomyopathy

Benign:1

Jul 06, 2017

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.013

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.4

PhyloP100

7.9

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-3.9

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.71

MVP

0.95

MPC

0.42

ClinPred

0.10

GERP RS

5.4

Varity_R

0.37

gMVP

0.68

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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