rs397517921
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000337.6(SGCD):βc.390delβ(p.Ala131ProfsTer2) 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 Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P129P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
SGCD
NM_000337.6 frameshift
NM_000337.6 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.136
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]
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ACMG classification
Classification made for transcript
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 5-156594935-CA-C is Pathogenic according to our data. Variant chr5-156594935-CA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 48118.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-156594935-CA-C is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCD | NM_000337.6 | c.390del | p.Ala131ProfsTer2 | frameshift_variant | 6/9 | ENST00000337851.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCD | ENST00000337851.9 | c.390del | p.Ala131ProfsTer2 | frameshift_variant | 6/9 | 1 | NM_000337.6 | P4 | |
SGCD | ENST00000435422.7 | c.387del | p.Ala130ProfsTer2 | frameshift_variant | 5/8 | 1 | A1 | ||
SGCD | ENST00000517913.5 | c.390del | p.Ala131ProfsTer2 | frameshift_variant | 8/10 | 5 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1449044Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0AN XY: 720718
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
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1449044
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29
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AN XY:
720718
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2F Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Feb 08, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 19, 2023 | This sequence change creates a premature translational stop signal (p.Ala131Profs*2) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 48118). For these reasons, this variant has been classified as Pathogenic. - |
Neuromuscular disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 23, 2012 | The Ala131fs variant (SGCD) has not been previously reported but has been identi fied by our laboratory in 1 individual with DCM without skeletal muscle involvem ent who carried other likely disease causing DCM variants. This variant is predi cted to cause a frameshift, which alters the protein's amino acid sequence begin ning at codon 131 and leads to a premature stop codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein (loss of function, LOF). Homozygous LOF variants in the SGCD gene have been reported in autosomal recessive Limb-Girdle muscular dystrophy (LGMD; OMIM, Human Gene Mu tation Database). The clinical significance of a heterozygous LOF variant for D CM in the absence of muscular dystrophy is unknown. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at