rs17314986

chr13-23250679-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000231.3(SGCG):c.347G>A(p.Arg116His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,611,016 control chromosomes in the GnomAD database, including 13,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (973 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12307 hom.)
• Consequence: SGCG NM_000231.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 3.16

Genes affected

SGCG (HGNC:10809): (sarcoglycan gamma) This gene encodes gamma-sarcoglycan, one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin. The dystrophin-glycoprotein complex (DGC) spans the sarcolemma and is comprised of dystrophin, syntrophin, alpha- and beta-dystroglycans and sarcoglycans. The DGC provides a structural link between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. Defects in the encoded protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C). [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a chain Gamma-sarcoglycan (size 290) in uniprot entity SGCG_HUMAN there are 38 pathogenic changes around while only 8 benign (83%) in NM_000231.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036991537).
• BP6: Variant 13-23250679-G-A is Benign according to our data. Variant chr13-23250679-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92655.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23250679-G-A is described in Lovd as [Benign]. Variant chr13-23250679-G-A is described in Lovd as [Likely_benign]. Variant chr13-23250679-G-A is described in Lovd as [Pathogenic].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCG	NM_000231.3	c.347G>A	p.Arg116His	missense_variant	4/8	ENST00000218867.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCG	ENST00000218867.4	c.347G>A	p.Arg116His	missense_variant	4/8	1	NM_000231.3	P1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15327 AN: 152054 Hom.: 973 Cov.: 33

Gnomad AFR AF: 0.0304

Gnomad AMI AF: 0.208

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.159

Gnomad EAS AF: 0.0123

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.123

GnomAD3 exomes AF: 0.112 AC: 28207 AN: 251024 Hom.: 1827 AF XY: 0.117 AC XY: 15889 AN XY: 135608

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.0875

Gnomad ASJ exome AF: 0.165

Gnomad EAS exome AF: 0.0129

Gnomad SAS exome AF: 0.129

Gnomad FIN exome AF: 0.154

Gnomad NFE exome AF: 0.130

Gnomad OTH exome AF: 0.127

GnomAD4 exome AF: 0.126 AC: 183159 AN: 1458844 Hom.: 12307 Cov.: 31 AF XY: 0.126 AC XY: 91775 AN XY: 725820

Gnomad4 AFR exome AF: 0.0281

Gnomad4 AMR exome AF: 0.0893

Gnomad4 ASJ exome AF: 0.164

Gnomad4 EAS exome AF: 0.0136

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.132

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.101 AC: 15322 AN: 152172 Hom.: 973 Cov.: 33 AF XY: 0.103 AC XY: 7666 AN XY: 74380

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.103

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.0123

Gnomad4 SAS AF: 0.130

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.122

Alfa AF: 0.124 Hom.: 2261

Bravo AF: 0.0931

TwinsUK AF: 0.126 AC: 467

ALSPAC AF: 0.135 AC: 521

ESP6500AA AF: 0.0304 AC: 134

ESP6500EA AF: 0.139 AC: 1198

ExAC AF: 0.110 AC: 13312

Asia WGS AF: 0.0690 AC: 240 AN: 3478

EpiCase AF: 0.134

EpiControl AF: 0.136

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 23, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Arg116His in exon 4 of SGCG: This variant is not expected to have clinical sig nificance because it has been identified in 14% (1198/8600) of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs17314986). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -

Autosomal recessive limb-girdle muscular dystrophy type 2C Benign:5

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Muscular dystrophy, limb-girdle, type 2C, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

Limb-Girdle Muscular Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Sarcoglycanopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.10
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Benign	0.034
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.79	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	0.77	P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.38
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.23
MPC		0.42
ClinPred		0.035	T
GERP RS		3.5
Varity_R		0.38
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17314986; hg19: chr13-23824818;