rs28936383

Positions:

• chr4-52028899-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_000232.5(SGCB):​c.452C>G​(p.Thr151Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,460 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 8.00

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 14 ACMG points.

• PM1: In a topological_domain Extracellular (size 231) in uniprot entity SGCB_HUMAN there are 66 pathogenic changes around while only 6 benign (92%) in NM_000232.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.903
• PP5: Variant 4-52028899-G-C is Pathogenic according to our data. Variant chr4-52028899-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-52028899-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCB	NM_000232.5	c.452C>G	p.Thr151Arg	missense_variant	4/6	ENST00000381431.10
SGCB	XM_047416074.1	c.242C>G	p.Thr81Arg	missense_variant	3/5
SGCB	XM_047416075.1	c.155C>G	p.Thr52Arg	missense_variant	3/5
SGCB	XM_047416076.1	c.155C>G	p.Thr52Arg	missense_variant	3/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCB	ENST00000381431.10	c.452C>G	p.Thr151Arg	missense_variant	4/6	1	NM_000232.5	P1
SGCB	ENST00000506357.5	c.*234C>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	5
SGCB	ENST00000514133.1	c.*247C>G		3_prime_UTR_variant, NMD_transcript_variant	4/4	5

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152034 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461426 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727054

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152034 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74224

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Dec 21, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1995	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	Feb 20, 2015	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Muscular dystrophy, limb-girdle, type 2E, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3 => Well-established functional studies show a deleterious effect (PMID:22095924) (PMID:9565988). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2023	This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 151 of the SGCB protein (p.Thr151Arg). This variant is present in population databases (rs28936383, gnomAD 0.007%). This missense change has been observed in individual(s) with limb-girdle muscular dystrophy (PMID: 7581448, 9565988, 21480868). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 8712). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SGCB protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects SGCB function (PMID: 22095924). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.65		Loss of ubiquitination at K152 (P = 0.0503);
MVP		1.0
MPC		0.35
ClinPred		0.93	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs28936383; hg19: chr4-52895065;