4-52038229-G-A

Position:

• chr4-52038229-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 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

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 18 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
• 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/exons	MANE	Protein	UniProt
SGCB	NM_000232.5	c.31C>T	p.Gln11*	stop_gained, splice_region_variant	1/6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.31C>T	p.Gln11*	stop_gained, splice_region_variant	1/5		XP_047272030.1

Ensembl

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

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

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

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 29, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	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. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 30, 2023	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2021	- -

Limb-girdle muscular dystrophy, recessive Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 27, 2016

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	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
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

Other links and lift over

dbSNP: rs752492870; hg19: chr4-52904395;