rs752492870

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1PM2PP3PP5_Very_Strong

The NM_000232.5(SGCB):c.31C>T(p.Gln11*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000312 in 1,282,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

SGCB
NM_000232.5 stop_gained, splice_region

Scores

Splicing: ADA: 0.9882

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.18

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 19 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 61 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 4-52038229-G-A is Pathogenic according to our data. Variant chr4-52038229-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-52038229-G-A is described in Lovd as [Pathogenic]. Variant chr4-52038229-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5 link	c.31C>T	p.Gln11*	stop_gained, splice_region_variant	Exon 1 of 6	ENST00000381431.10	NP_000223.1	Q16585-1Q5U0N0
SGCB	XM_047416074.1 link	c.31C>T	p.Gln11*	stop_gained, splice_region_variant	Exon 1 of 5		XP_047272030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10 link	c.31C>T	p.Gln11*	stop_gained, splice_region_variant	Exon 1 of 6	1	NM_000232.5	ENSP00000370839.6		Q16585-1
SGCB	ENST00000506357.5 link	n.16C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 1 of 5	5		ENSP00000421235.1		H0Y8J3

Frequencies

GnomAD3 genomes

AF:

0.0000331

AC:

AN:

151094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000309

AC:

AN:

1131718

Hom.:

Cov.:

AF XY:

0.0000311

AC XY:

AN XY:

546398

show subpopulations

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:

0.0000350

Gnomad4 OTH exome

AF:

0.0000445

GnomAD4 genome

AF:

0.0000331

AC:

AN:

151094

Hom.:

Cov.:

AF XY:

0.0000407

AC XY:

AN XY:

73772

show subpopulations

Gnomad4 AFR

AF:

0.0000242

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:

0.0000591

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E

Pathogenic:4

Jan 30, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 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.Gln11*) 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 present in population databases (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with limb girdle muscular dystrophy (PMID: 9032047, 10993494, 19770540). ClinVar contains an entry for this variant (Variation ID: 284502). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 22, 2021

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 29, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Nov 05, 2015

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Limb-girdle muscular dystrophy, recessive

Pathogenic:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31C>T (p.Gln11Ter) variant is a stop-gained variant that has been described in four studies, in which it is found in a compound heterozygous state in four limb-girdle muscular dystrophy patients (Duggan et al. 1997; Ginjaar et al. 2000; Love et al. 2004; Khadilkar et al. 2009). Control data are unavailable for this variant which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the potential impact of stop-gained variants and evidence from the literature the p.Gln11Ter variant is classified as likely pathogenic for recessive limb-girdle muscular dystrophy. -

Qualitative or quantitative defects of beta-sarcoglycan

Pathogenic:1

Sep 27, 2016

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SGCB c.31C>T (p.Gln11Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. This variant has been described in four studies, in which it is found in a compound heterozygous state in four unrelated individuals with beta-sarcoglycanopathy, or limb-girdle muscular dystrophy type 2E (Duggan et al. 1997; Ginjaar et al. 2000; Love et al. 2004; Khadilkar et al. 2009). Control data are unavailable for this variant, which is not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. Based on the evidence from the literature and the potential impact of stop-gained variants, the p.Gln11Ter variant is classified as likely pathogenic for beta-sarcoglycanopathy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Benign

0.15

Vest4

0.35

GERP RS

3.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.80

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over