rs17314986

Positions:

chr13-23250679-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000218867.4(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
ENST00000218867.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 3.16

Variant links:

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]

SGCG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 ENST00000218867.4

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	Protein	UniProt
SGCG	NM_000231.3 linkuse as main transcript	c.347G>A	p.Arg116His	missense_variant	4/8	ENST00000218867.4	NP_000222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4 linkuse as main transcript	c.347G>A	p.Arg116His	missense_variant	4/8	1	NM_000231.3	ENSP00000218867	P1

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15327

AN:

152054

Hom.:

973

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.126

AC XY:

91775

AN XY:

725820

show subpopulations

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.:

AF XY:

0.103

AC XY:

7666

AN XY:

74380

show subpopulations

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:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

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	-	- -
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	Athena Diagnostics	Apr 23, 2021	- -
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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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. -
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	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

Eigen

Benign

0.034

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.74

MutationAssessor

Pathogenic

3.1

MutationTaster

Benign

0.77

P;P;P

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.38

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.23

MPC

0.42

ClinPred

0.035

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over