rs796065318

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000023.4(SGCA):​c.981_982dup​(p.Asp328AlafsTer90) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000071 in 1,407,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S327S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

SGCA
NM_000023.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 0.129
Variant links:
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 17-50170663-C-CCG is Pathogenic according to our data. Variant chr17-50170663-C-CCG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SGCANM_000023.4 linkuse as main transcriptc.981_982dup p.Asp328AlafsTer90 frameshift_variant 8/10 ENST00000262018.8
SGCANM_001135697.3 linkuse as main transcriptc.609_610dup p.Asp204AlafsTer90 frameshift_variant 6/8
SGCANR_135553.2 linkuse as main transcriptn.808_809dup non_coding_transcript_exon_variant 7/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SGCAENST00000262018.8 linkuse as main transcriptc.981_982dup p.Asp328AlafsTer90 frameshift_variant 8/101 NM_000023.4 P1Q16586-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.10e-7
AC:
1
AN:
1407948
Hom.:
0
Cov.:
30
AF XY:
0.00000144
AC XY:
1
AN XY:
695190
show subpopulations
Gnomad4 AFR exome
AF:
0.0000311
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
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.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:3
Likely pathogenic, criteria provided, single submitterclinical testingInvitaeDec 19, 2022In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 191294). This variant is also known as c.608_609insCG. This frameshift has been observed in individual(s) with clinical features of limb girdle muscular dystrophy (PMID: 27671536; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the SGCA gene (p.Asp328Alafs*90). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 60 amino acid(s) of the SGCA protein and extend the protein by 29 additional amino acid residues. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 27, 2022- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 29, 2024- -
not provided Pathogenic:1
Likely pathogenic, flagged submissionresearchCenter for Genomic Medicine, King Faisal Specialist Hospital and Research Center-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs796065318; hg19: chr17-48248024; API