rs886044103

Positions:

• chr4-52038245-C-CGCCGCT

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BS1_Supporting

The ENST00000381431.10(SGCB):​c.14_15insAGCGGC​(p.Ala8_Ala9dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000758 in 1,292,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A5A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: SGCB ENST00000381431.10 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 0.763

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00035 (53/151516) while in subpopulation AMR AF= 0.00335 (51/15208). AF 95% confidence interval is 0.00262. There are 0 homozygotes in gnomad4. There are 35 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCB	NM_000232.5	c.14_15insAGCGGC	p.Ala8_Ala9dup	inframe_insertion	1/6	ENST00000381431.10	NP_000223.1
SGCB	XM_047416074.1	c.14_15insAGCGGC	p.Ala8_Ala9dup	inframe_insertion	1/5		XP_047272030.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCB	ENST00000381431.10	c.14_15insAGCGGC	p.Ala8_Ala9dup	inframe_insertion	1/6	1	NM_000232.5	ENSP00000370839	P1
SGCB	ENST00000506357.5			upstream_gene_variant		5		ENSP00000421235

Frequencies

GnomAD3 genomes AF: 0.000350 AC: 53 AN: 151408 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00336

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000394 AC: 45 AN: 1141434 Hom.: 0 Cov.: 31 AF XY: 0.0000453 AC XY: 25 AN XY: 551522

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000281

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000158

Gnomad4 OTH exome AF: 0.000286

GnomAD4 genome AF: 0.000350 AC: 53 AN: 151516 Hom.: 0 Cov.: 32 AF XY: 0.000473 AC XY: 35 AN XY: 74044

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00335

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000169 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2020	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 25, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	This variant, c.9_14dup, results in the insertion of 2 amino acid(s) of the SGCB protein (p.Ala8_Ala9dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SGCB-related conditions. ClinVar contains an entry for this variant (Variation ID: 420206). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs886044103; hg19: chr4-52904411;