4-52038229-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1 PP2 BS1_Supporting

The NM_000232.5(SGCB):​c.31C>G​(p.Gln11Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000437 in 1,282,918 control chromosomes in the GnomAD database, including 1 homozygotes. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q11R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000045 (1 hom.)
• Consequence: SGCB NM_000232.5 missense, splice_region
• Scores: Splicing: ADA: 0.006266
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U: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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000232.5
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: -0.0049736 (below the threshold of 3.09). Trascript score misZ: -0.4279 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive limb-girdle muscular dystrophy type 2E, autosomal recessive limb-girdle muscular dystrophy.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000451 (51/1131718) while in subpopulation SAS AF = 0.00142 (49/34570). AF 95% confidence interval is 0.0011. There are 1 homozygotes in GnomAdExome4. There are 36 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000232.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	NM_000232.5	MANE Select	c.31C>G	p.Gln11Glu	missense splice_region	Exon 1 of 6	NP_000223.1
	SGCB	NM_001440519.1		c.31C>G	p.Gln11Glu	missense splice_region	Exon 1 of 5	NP_001427448.1
	SGCB	NM_001440520.1		c.-377C>G		splice_region	Exon 1 of 7	NP_001427449.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCB	ENST00000381431.10	TSL:1 MANE Select	c.31C>G	p.Gln11Glu	missense splice_region	Exon 1 of 6	ENSP00000370839.6
	SGCB	ENST00000506357.5	TSL:5	n.16C>G		splice_region non_coding_transcript_exon	Exon 1 of 5	ENSP00000421235.1

Frequencies

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

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: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000233 AC: 9 AN: 38616 AF XY: 0.000313

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000451 AC: 51 AN: 1131718 Hom.: 1 Cov.: 31 AF XY: 0.0000659 AC XY: 36 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: 0.00142 AC: 49 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: 0.00 AC: 0 AN: 944084

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

GnomAD4 genome AF: 0.0000331 AC: 5 AN: 151200 Hom.: 0 Cov.: 32 AF XY: 0.0000677 AC XY: 5 AN XY: 73890

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15196

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5106

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67634

Other (OTH) AF: 0.00 AC: 0 AN: 2098

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.000335 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:1 Uncertain:5

Mar 21, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense c.31C>G(p.Gln11Glu) variant lying in splice region of SGCB gene has been reported previously in individuals affected with muscular dystrophies and myopathies (Soheili T, et al., 2012; Duggan DJ, et al., 1997). Functional studies show that this variant disrupted membrane localization of the protein and affects SGCB function (Soheili T, et al., 2012). The p.Gln11Glu variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance (multiple submissions). The amino acid change p.Gln11Glu in SGCB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gln at position 11 is changed to a Glu changing protein sequence and it might alter its composition and physico-chemical properties. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 11 of the SGCB protein (p.Gln11Glu). This variant is present in population databases (rs752492870, gnomAD 0.1%). This missense change has been observed in individual(s) with sarcoglycan deficiency (PMID: 9032047). ClinVar contains an entry for this variant (Variation ID: 282248). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SGCB function (PMID: 22095924). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Oct 21, 2022

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous missense variation in exon 1 of the SGCB gene that results in the amino acid substitution of Glutamic Acid for Glutamine at codon 11 (p.Gln11Glu) was detected. This variant c.31C>G (p.Gln11Glu) has not been reported in the 1000 genomes databases. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as uncertain significance.

Feb 20, 2025

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:2

Oct 08, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional analysis of transfected cells showed that Q11E disrupted localization of the SGCB protein to the cell membrane (Soheili et al., 2012); Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 9032047, 30564623, 22095924)

Jun 06, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1

Apr 24, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SGCB c.31C>G (p.Gln11Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00023 in 38616 control chromosomes. c.31C>G has been reported in the literature in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive (example, Duggan_1997, Soheilli_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no quantitative experimental evidence demonstrating an impact on protein function has been reported, although it has been demonstrated to impair membrane localization of Sarcoglycans in vitro (Soheilli_2012). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	19
DANN	Benign	0.67
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.11	N
REVEL	Uncertain	0.52
Sift	Benign	0.21	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.66
MutPred		0.42		Loss of MoRF binding (P = 0.0467)
MVP		0.86
MPC		0.068
ClinPred		0.041	T
GERP RS		3.0
PromoterAI		0.049	Neutral
Varity_R		0.12
gMVP		0.23
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0063
dbscSNV1_RF	Benign	0.11
SpliceAI score (max)		0.040		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;