rs1057517377
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000023.4(SGCA):βc.754_755delβ(p.Lys252ValfsTer8) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.0000014 ( 0 hom. )
Consequence
SGCA
NM_000023.4 frameshift
NM_000023.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.24
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]
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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 17-50170148-TAA-T is Pathogenic according to our data. Variant chr17-50170148-TAA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50170148-TAA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCA | NM_000023.4 | c.754_755del | p.Lys252ValfsTer8 | frameshift_variant | 7/10 | ENST00000262018.8 | |
SGCA | NM_001135697.3 | c.585-491_585-490del | intron_variant | ||||
SGCA | NR_135553.2 | n.784-491_784-490del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCA | ENST00000262018.8 | c.754_755del | p.Lys252ValfsTer8 | frameshift_variant | 7/10 | 1 | NM_000023.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461708Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727160
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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 2D Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 15, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 20, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 19, 2022 | - - |
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