rs762412447

chr4-52029752-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The NM_000232.5(SGCB):c.355A>T(p.Ile119Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000684 in 1,461,582 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I119N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: SGCB NM_000232.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6
• Conservation: PhyloP100: 5.84

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 Likely_pathogenic. Variant got 9 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-52029751-A-T is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• PP5: Variant 4-52029752-T-A is Pathogenic according to our data. Variant chr4-52029752-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282249.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=6, Likely_pathogenic=2}. Variant chr4-52029752-T-A is described in Lovd as [Pathogenic]. Variant chr4-52029752-T-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCB	NM_000232.5	c.355A>T	p.Ile119Phe	missense_variant	3/6	ENST00000381431.10
SGCB	XM_047416074.1	c.145A>T	p.Ile49Phe	missense_variant	2/5
SGCB	XM_047416075.1	c.58A>T	p.Ile20Phe	missense_variant	2/5
SGCB	XM_047416076.1	c.58A>T	p.Ile20Phe	missense_variant	2/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCB	ENST00000381431.10	c.355A>T	p.Ile119Phe	missense_variant	3/6	1	NM_000232.5	P1
SGCB	ENST00000506357.5	c.*137A>T		3_prime_UTR_variant, NMD_transcript_variant	4/5	5
SGCB	ENST00000514133.1	c.*150A>T		3_prime_UTR_variant, NMD_transcript_variant	3/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251470 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135904

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 SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461582 Hom.: 0 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 727110

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: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 24, 2022	- -
Likely pathogenic, flagged submission	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	-	A heterozygous missense variation in exon 3 of the SGCB gene that results in the amino acid substitution of Phenylalanine for Isoleucine at codon 119 was detected.This variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 10, 2023	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. This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 119 of the SGCB protein (p.Ile119Phe). This variant is present in population databases (rs762412447, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of limb-girdle muscular dystrophy (PMID: 9565988, 27671536, 34925456, 35416532). ClinVar contains an entry for this variant (Variation ID: 282249). 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. This variant disrupts the p.Ile119 amino acid residue in SGCB. Other variant(s) that disrupt this residue have been observed in individuals with SGCB-related conditions (PMID: 29970176), which suggests that this may be a clinically significant amino acid residue. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 01, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant c.355A>T (p.Ile119Phe) in SGCB gene has been reported in individual(s) affected with muscular dystrophy (Monies D et.al.,2016) . This variant has been reported to the ClinVar database as Uncertain Significance. The p.Ile119Phe variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00001988% is reported in gnomAD. The amino acid Ile at position 119 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Ile119Phe in SGCB is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 08, 2021	Not observed at significant frequency in large population cohorts (Lek et al., 2016); 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: 9565988, 8968749, 30564623, 27671536) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Uncertain	24
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.21	T
Polyphen		0.92	P
Vest4		0.93
MutPred		0.63		Loss of catalytic residue at P121 (P = 0.0303);
MVP		1.0
MPC		0.37
ClinPred		0.53	D
GERP RS		5.3
Varity_R		0.30
gMVP		0.84

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: rs762412447; hg19: chr4-52895918;