17-50169181-G-A

Position:

• chr17-50169181-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The ENST00000262018.8(SGCA):​c.674G>A​(p.Gly225Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G225G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SGCA ENST00000262018.8 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.04

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a topological_domain Extracellular (size 266) in uniprot entity SGCA_HUMAN there are 171 pathogenic changes around while only 10 benign (94%) in ENST00000262018.8
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCA	NM_000023.4	c.674G>A	p.Gly225Asp	missense_variant	6/10	ENST00000262018.8	NP_000014.1
SGCA	NM_001135697.3	c.584+609G>A		intron_variant			NP_001129169.1
SGCA	NR_135553.2	n.710G>A		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCA	ENST00000262018.8	c.674G>A	p.Gly225Asp	missense_variant	6/10	1	NM_000023.4	ENSP00000262018	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2D Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2020	This variant is not present in population databases (ExAC no frequency). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The aspartic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with SGCA-related disease. ClinVar contains an entry for this variant (Variation ID: 290718). This sequence change replaces glycine with aspartic acid at codon 225 of the SGCA protein (p.Gly225Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 06, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.64
Sift	Benign	0.15	T
Sift4G	Benign	0.32	T
Polyphen		0.99	D
Vest4		0.31
MutPred		0.49		Loss of glycosylation at P227 (P = 0.0882);
MVP		1.0
MPC		0.48
ClinPred		0.83	D
GERP RS		4.2
Varity_R		0.14
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886044540; hg19: chr17-48246542;