rs1800350

Positions:

• chr13-23234643-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000231.3(SGCG):​c.228T>C​(p.Asp76Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,610,324 control chromosomes in the GnomAD database, including 13,336 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1990 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11346 hom.)
• Consequence: SGCG NM_000231.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.46

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 13-23234643-T-C is Benign according to our data. Variant chr13-23234643-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 92653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23234643-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.46 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCG	NM_000231.3	c.228T>C	p.Asp76Asp	synonymous_variant	3/8	ENST00000218867.4	NP_000222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4	c.228T>C	p.Asp76Asp	synonymous_variant	3/8	1	NM_000231.3	ENSP00000218867.3

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22276 AN: 151854 Hom.: 1988 Cov.: 32

Gnomad AFR AF: 0.249

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0780

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.122

Gnomad OTH AF: 0.130

GnomAD3 exomes AF: 0.105 AC: 26294 AN: 251362 Hom.: 1823 AF XY: 0.104 AC XY: 14163 AN XY: 135866

Gnomad AFR exome AF: 0.253

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.000815

Gnomad SAS exome AF: 0.102

Gnomad FIN exome AF: 0.0795

Gnomad NFE exome AF: 0.118

Gnomad OTH exome AF: 0.106

GnomAD4 exome AF: 0.118 AC: 172428 AN: 1458354 Hom.: 11346 Cov.: 31 AF XY: 0.117 AC XY: 84883 AN XY: 725660

Gnomad4 AFR exome AF: 0.252

Gnomad4 AMR exome AF: 0.0614

Gnomad4 ASJ exome AF: 0.129

Gnomad4 EAS exome AF: 0.000429

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.0843

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.120

GnomAD4 genome AF: 0.147 AC: 22283 AN: 151970 Hom.: 1990 Cov.: 32 AF XY: 0.141 AC XY: 10438 AN XY: 74288

Gnomad4 AFR AF: 0.248

Gnomad4 AMR AF: 0.102

Gnomad4 ASJ AF: 0.125

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.0780

Gnomad4 NFE AF: 0.122

Gnomad4 OTH AF: 0.128

Alfa AF: 0.132 Hom.: 1104

Bravo AF: 0.154

Asia WGS AF: 0.0640 AC: 224 AN: 3478

EpiCase AF: 0.118

EpiControl AF: 0.118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Asp76Asp in exon 3 of SGCG: This variant is not expected to have clinical sign ificance because it has been identified in 24% (1040/4406) of African American c hromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/E VS/; dbSNP rs1800350). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 16, 2012	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 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. -

Autosomal recessive limb-girdle muscular dystrophy type 2C Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

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 12, 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
BayesDel_noAF	Benign	-0.56
CADD	Benign	3.7
DANN	Benign	0.44

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: rs1800350; hg19: chr13-23808782;