rs752492870

Variant names:

• chr4-52038229-G-A
• rs752492870
• NM_000232.5:c.31C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-52038229-G-A
• chr4-52038229-G-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_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
• Publications: 5 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 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 84 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 284502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCB	NM_000232.5	c.31C>T	p.Gln11*	stop_gained, splice_region_variant	Exon 1 of 6	ENST00000381431.10	NP_000223.1
SGCB	NM_001440519.1	c.31C>T	p.Gln11*	stop_gained, splice_region_variant	Exon 1 of 5		NP_001427448.1
SGCB	NM_001440520.1	c.-377C>T		splice_region_variant	Exon 1 of 7		NP_001427449.1
SGCB	NM_001440520.1	c.-377C>T		5_prime_UTR_variant	Exon 1 of 7		NP_001427449.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0000331 AC: 5 AN: 151094 Hom.: 0 Cov.: 32

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: 35 AN: 1131718 Hom.: 0 Cov.: 31 AF XY: 0.0000311 AC XY: 17 AN XY: 546398

African (AFR) AF: 0.00 AC: 0 AN: 23506

American (AMR) AF: 0.00 AC: 0 AN: 16664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16722

East Asian (EAS) AF: 0.00 AC: 0 AN: 24618

South Asian (SAS) AF: 0.00 AC: 0 AN: 34570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3054

European-Non Finnish (NFE) AF: 0.0000350 AC: 33 AN: 944084

Other (OTH) AF: 0.0000445 AC: 2 AN: 44950

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 151094 Hom.: 0 Cov.: 32 AF XY: 0.0000407 AC XY: 3 AN XY: 73772

African (AFR) AF: 0.0000242 AC: 1 AN: 41276

American (AMR) AF: 0.00 AC: 0 AN: 15176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5122

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10280

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.0000591 AC: 4 AN: 67644

Other (OTH) AF: 0.00 AC: 0 AN: 2076

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

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

- -

Feb 29, 2024

Baylor Genetics

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

- -

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

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.15	N
PhyloP100		1.2
Vest4		0.35
GERP RS		3.0
PromoterAI		0.10	Neutral
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs752492870; hg19: chr4-52904395;