rs1554094947

Positions:

• chr5-156344556-A-AGGTG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000337.6(SGCD):​c.74_77dup​(p.Ile27GlyfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGCD NM_000337.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.10

Genes affected

SGCD (HGNC:10807): (sarcoglycan delta) The protein encoded by this gene is one of the four known components of the sarcoglycan complex, which is a subcomplex of the dystrophin-glycoprotein complex (DGC). DGC forms a link between the F-actin cytoskeleton and the extracellular matrix. This protein is expressed most abundantly in skeletal and cardiac muscle. Mutations in this gene have been associated with autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Jul 2008]

LOC124901120 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-156344556-A-AGGTG is Pathogenic according to our data. Variant chr5-156344556-A-AGGTG is described in ClinVar as [Pathogenic]. Clinvar id is 411697.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCD	NM_000337.6	c.74_77dup	p.Ile27GlyfsTer40	frameshift_variant	3/9	ENST00000337851.9	NP_000328.2
LOC124901120	XR_007059016.1	n.234+2896_234+2897insCACC		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCD	ENST00000337851.9	c.74_77dup	p.Ile27GlyfsTer40	frameshift_variant	3/9	1	NM_000337.6	ENSP00000338343	P4
SGCD	ENST00000435422.7	c.71_74dup	p.Ile26GlyfsTer40	frameshift_variant	2/8	1		ENSP00000403003	A1
SGCD	ENST00000517913.5	c.74_77dup	p.Ile27GlyfsTer40	frameshift_variant	5/10	5		ENSP00000429378
SGCD	ENST00000524347.2	c.74_77dup	p.Ile27GlyfsTer40	frameshift_variant, NMD_transcript_variant	3/6	5		ENSP00000430794

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2F Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 11, 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 create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 411697). This variant has not been reported in the literature in individuals affected with SGCD-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile27Glyfs*40) in the SGCD gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCD are known to be pathogenic (PMID: 8841194, 10735275, 10838250). -

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: rs1554094947; hg19: chr5-155771566;