rs1555568396

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate

The NM_000023.4(SGCA):​c.290A>G​(p.Asp97Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SGCA
NM_000023.4 missense

Scores

7
7
5

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.74
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 10 ACMG points.

PM1
In a topological_domain Extracellular (size 266) in uniprot entity SGCA_HUMAN there are 108 pathogenic changes around while only 2 benign (98%) in NM_000023.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.946
PP5
Variant 17-50167714-A-G is Pathogenic according to our data. Variant chr17-50167714-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549996.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr17-50167714-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SGCANM_000023.4 linkc.290A>G p.Asp97Gly missense_variant Exon 3 of 10 ENST00000262018.8 NP_000014.1 Q16586-1A0A0S2Z4Q1
SGCANM_001135697.3 linkc.290A>G p.Asp97Gly missense_variant Exon 3 of 8 NP_001129169.1 Q16586-2A0A0S2Z4P8
SGCANR_135553.2 linkn.326A>G non_coding_transcript_exon_variant Exon 3 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SGCAENST00000262018.8 linkc.290A>G p.Asp97Gly missense_variant Exon 3 of 10 1 NM_000023.4 ENSP00000262018.3 Q16586-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Pathogenic:1
Apr 21, 2017
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.50
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.85
.;D
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.81
T;T
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.95
D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-2.1
N;N
REVEL
Pathogenic
0.79
Sift
Uncertain
0.029
D;D
Sift4G
Benign
0.15
T;T
Polyphen
1.0
D;D
Vest4
0.65
MutPred
0.83
Gain of loop (P = 0.0312);Gain of loop (P = 0.0312);
MVP
1.0
MPC
0.69
ClinPred
0.89
D
GERP RS
4.5
Varity_R
0.22
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.32
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.32
Position offset: -1

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: rs1555568396; hg19: chr17-48245075; API