rs1800351

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000231.3(SGCG):c.312T>G(p.Leu104=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.399 in 1,602,866 control chromosomes in the GnomAD database, including 134,611 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L104L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.47 ( 18343 hom., cov: 32)

Exomes 𝑓: 0.39 ( 116268 hom. )

Consequence

SGCG
NM_000231.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.711

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 13-23250644-T-G is Benign according to our data. Variant chr13-23250644-T-G is described in ClinVar as [Benign]. Clinvar id is 92654.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23250644-T-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.711 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCG	NM_000231.3 linkuse as main transcript	c.312T>G	p.Leu104=	synonymous_variant	4/8	ENST00000218867.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCG	ENST00000218867.4 linkuse as main transcript	c.312T>G	p.Leu104=	synonymous_variant	4/8	1	NM_000231.3	P1

Frequencies

GnomAD3 genomes

AF:

0.469

AC:

71218

AN:

151864

Hom.:

18319

Cov.:

show subpopulations

Gnomad AFR

AF:

0.678

Gnomad AMI

AF:

0.300

Gnomad AMR

AF:

0.379

Gnomad ASJ

AF:

0.334

Gnomad EAS

AF:

0.686

Gnomad SAS

AF:

0.375

Gnomad FIN

AF:

0.400

Gnomad MID

AF:

0.256

Gnomad NFE

AF:

0.375

Gnomad OTH

AF:

0.402

GnomAD3 exomes

AF:

0.419

AC:

105004

AN:

250602

Hom.:

23264

AF XY:

0.409

AC XY:

55408

AN XY:

135448

show subpopulations

Gnomad AFR exome

AF:

0.685

Gnomad AMR exome

AF:

0.380

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.684

Gnomad SAS exome

AF:

0.377

Gnomad FIN exome

AF:

0.400

Gnomad NFE exome

AF:

0.375

Gnomad OTH exome

AF:

0.374

GnomAD4 exome

AF:

0.392

AC:

568812

AN:

1450884

Hom.:

116268

Cov.:

AF XY:

0.390

AC XY:

281664

AN XY:

722524

show subpopulations

Gnomad4 AFR exome

AF:

0.684

Gnomad4 AMR exome

AF:

0.379

Gnomad4 ASJ exome

AF:

0.335

Gnomad4 EAS exome

AF:

0.701

Gnomad4 SAS exome

AF:

0.376

Gnomad4 FIN exome

AF:

0.405

Gnomad4 NFE exome

AF:

0.375

Gnomad4 OTH exome

AF:

0.404

GnomAD4 genome

AF:

0.469

AC:

71295

AN:

151982

Hom.:

18343

Cov.:

AF XY:

0.465

AC XY:

34553

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.677

Gnomad4 AMR

AF:

0.379

Gnomad4 ASJ

AF:

0.334

Gnomad4 EAS

AF:

0.685

Gnomad4 SAS

AF:

0.375

Gnomad4 FIN

AF:

0.400

Gnomad4 NFE

AF:

0.375

Gnomad4 OTH

AF:

0.408

Alfa

AF:

0.395

Hom.:

16157

Bravo

AF:

0.482

EpiCase

AF:

0.353

EpiControl

AF:

0.348

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	p.Leu104Leu in exon 4 of SGCG: This variant is not expected to have clinical sig nificance because it has been identified in 67% (2958/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/ EVS/; dbSNP rs1800351). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 13, 2013	- -

Autosomal recessive limb-girdle muscular dystrophy type 2C

Benign:4

Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Limb-Girdle Muscular Dystrophy, Recessive

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Apr 14, 2017

- -

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

-0.57

Cadd

Benign

5.1

Dann

Benign

0.61

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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