rs574376340
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000023.4(SGCA):c.541C>A(p.Arg181Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 1,575,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R181C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000023.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCA | NM_000023.4 | c.541C>A | p.Arg181Ser | missense_variant | 5/10 | ENST00000262018.8 | |
SGCA | NM_001135697.3 | c.541C>A | p.Arg181Ser | missense_variant | 5/8 | ||
SGCA | NR_135553.2 | n.577C>A | non_coding_transcript_exon_variant | 5/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCA | ENST00000262018.8 | c.541C>A | p.Arg181Ser | missense_variant | 5/10 | 1 | NM_000023.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 3AN: 187924Hom.: 0 AF XY: 0.0000199 AC XY: 2AN XY: 100256
GnomAD4 exome AF: 0.00000632 AC: 9AN: 1423802Hom.: 0 Cov.: 33 AF XY: 0.00000426 AC XY: 3AN XY: 704482
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74318
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jun 13, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 2020 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 20, 2022 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 181 of the SGCA protein (p.Arg181Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SGCA-related conditions. ClinVar contains an entry for this variant (Variation ID: 288595). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGCA protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 27, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at