rs104893868

Positions:

• chr4-52028799-A-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000381431.10(SGCB):​c.552T>G​(p.Tyr184Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCB ENST00000381431.10 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.455

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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-52028799-A-C is Pathogenic according to our data. Variant chr4-52028799-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 8713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-52028799-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCB	NM_000232.5	c.552T>G	p.Tyr184Ter	stop_gained	4/6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.342T>G	p.Tyr114Ter	stop_gained	3/5		XP_047272030.1
SGCB	XM_047416075.1	c.255T>G	p.Tyr85Ter	stop_gained	3/5		XP_047272031.1
SGCB	XM_047416076.1	c.255T>G	p.Tyr85Ter	stop_gained	3/5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.552T>G	p.Tyr184Ter	stop_gained	4/6	1	NM_000232.5	ENSP00000370839	P1
SGCB	ENST00000506357.5	c.*334T>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	5		ENSP00000421235
SGCB	ENST00000514133.1			downstream_gene_variant		5		ENSP00000425818

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2E Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 8713). This premature translational stop signal has been observed in individual(s) with SGCB-related conditions (PMID: 7581449, 9032047, 12868499, 25862795). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr184*) 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). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1995	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 29, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Benign	-0.012
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.88	D
MutationTaster	Benign	1.0	A;A
Vest4		0.85
GERP RS		-4.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs104893868; hg19: chr4-52894965;