NM_000023.4:c.391delC

Variant names:

• chr17-50168374-GC-G
• rs144356125
• NM_000023.4:c.391delC

Variant summary

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

The NM_000023.4(SGCA):​c.391delC​(p.Leu131CysfsTer80) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,413,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SGCA NM_000023.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -0.548

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [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 17-50168374-GC-G is Pathogenic according to our data. Variant chr17-50168374-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 418990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCA	NM_000023.4	c.391delC	p.Leu131CysfsTer80	frameshift_variant	Exon 5 of 10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.391delC	p.Leu131CysfsTer66	frameshift_variant	Exon 5 of 8		NP_001129169.1
SGCA	NR_135553.2	n.427delC		non_coding_transcript_exon_variant	Exon 5 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.391delC	p.Leu131CysfsTer80	frameshift_variant	Exon 5 of 10	1	NM_000023.4	ENSP00000262018.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000141 AC: 2 AN: 1413970 Hom.: 0 Cov.: 33 AF XY: 0.00000143 AC XY: 1 AN XY: 699044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000268

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000269

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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 2D Pathogenic:2

Aug 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 418990). This variant has not been reported in the literature in individuals affected with SGCA-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu131Cysfs*80) in the SGCA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SGCA are known to be pathogenic (PMID: 9192266). -

Feb 08, 2023

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 07, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.391delC deletion in the SGCA gene causes a frameshift starting with codon Leucine 131, changes thisamino acid to a Cysteine residue and creates a premature Stop codon at position 80 of the new reading frame,denoted p.Leu131CysfsX80. This variant is predicted to cause loss of normal protein function either throughprotein truncation or nonsense-mediated mRNA decay. Therefore, we interpret the c.391delC as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs144356125; hg19: chr17-48245735;