rs28936383
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_000232.5(SGCB):āc.452C>Gā(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 (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
SGCB
NM_000232.5 missense
NM_000232.5 missense
Scores
8
9
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
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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: 2AN: 152034Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461426Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727054
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 152034Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74224
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of ubiquitination at K152 (P = 0.0503);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at