chr4-52029852-AAC-A

Position:

• chr4-52029852-AAC-A

Variant summary

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

The NM_000232.5(SGCB):​c.253_254delGT​(p.Val85fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCB NM_000232.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.07

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 4-52029852-AAC-A is Pathogenic according to our data. Variant chr4-52029852-AAC-A is described in ClinVar as [Pathogenic]. Clinvar id is 466602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCB	NM_000232.5	c.253_254delGT	p.Val85fs	frameshift_variant	3/6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.43_44delGT	p.Val15fs	frameshift_variant	2/5		XP_047272030.1
SGCB	XM_047416075.1	c.-45_-44delGT		5_prime_UTR_variant	2/5		XP_047272031.1
SGCB	XM_047416076.1	c.-45_-44delGT		5_prime_UTR_variant	2/5		XP_047272032.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.253_254delGT	p.Val85fs	frameshift_variant	3/6	1	NM_000232.5	ENSP00000370839.6

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: 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	Revvity Omics, Revvity	Jul 09, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 12, 2016	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in SGCB are known to be pathogenic (PMID: 18285821). This sequence change deletes 2 nucleotides in exon 3 of the SGCB mRNA (c.253_254delGT), causing a frameshift at codon 85. This creates a premature translational stop signal (p.Val85Tyrfs*13) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

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: rs1553940274; hg19: chr4-52896018;