rs1555569038
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000023.4(SGCA):c.727G>A(p.Asp243Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,556 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
SGCA
NM_000023.4 missense
NM_000023.4 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 4.30
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000023.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCA | NM_000023.4 | c.727G>A | p.Asp243Asn | missense_variant | 6/10 | ENST00000262018.8 | |
SGCA | NM_001135697.3 | c.584+662G>A | intron_variant | ||||
SGCA | NR_135553.2 | n.763G>A | non_coding_transcript_exon_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCA | ENST00000262018.8 | c.727G>A | p.Asp243Asn | missense_variant | 6/10 | 1 | NM_000023.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 genomes
?
Cov.:
31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461556Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727072
GnomAD4 exome
AF:
AC:
1
AN:
1461556
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
727072
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 31
GnomAD4 genome
?
Cov.:
31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 14, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
MutationTaster
Benign
D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Gain of sheet (P = 0.0827);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at