13-23234650-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000231.3(SGCG):c.235C>T(p.Arg79Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000139 in 1,611,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R79H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

SGCG
NM_000231.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:7

Conservation

PhyloP100: 3.46

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive limb-girdle muscular dystrophy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive limb-girdle muscular dystrophy type 2C
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Ambry Genetics

SGCG links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23059934).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCG	NM_000231.3 link	c.235C>T	p.Arg79Cys	missense_variant	Exon 3 of 8	ENST00000218867.4	NP_000222.2	Q13326

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4 link	c.235C>T	p.Arg79Cys	missense_variant	Exon 3 of 8	1	NM_000231.3	ENSP00000218867.3		Q13326

Frequencies

GnomAD3 genomes

AF:

0.000272

AC:

AN:

150868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000536

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000528

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00155

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000310

AC:

AN:

251366

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.000838

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00185

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000125

AC:

183

AN:

1460700

Hom.:

Cov.:

AF XY:

0.000131

AC XY:

AN XY:

726734

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33432

American (AMR)

AF:

0.000738

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.00109

AC:

AN:

39628

South Asian (SAS)

AF:

0.000162

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000711

AC:

AN:

1111080

Other (OTH)

AF:

0.0000994

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000272

AC:

AN:

150980

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

AN XY:

73668

show subpopulations

African (AFR)

AF:

0.000534

AC:

AN:

41192

American (AMR)

AF:

0.000528

AC:

AN:

15164

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00155

AC:

AN:

5148

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67838

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000128

Hom.:

Bravo

AF:

0.000321

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000222

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2C

Uncertain:4

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 79 of the SGCG protein (p.Arg79Cys). This variant is present in population databases (rs148404730, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with SGCG-related conditions. ClinVar contains an entry for this variant (Variation ID: 285054). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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. -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 04, 2021

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NM_000231.2(SGCG):c.235C>T(R79C) is a missense variant classified as a variant of uncertain significance in the context of gamma-sarcoglycanopathy. R79C has been observed in cases with relevant disease (PMID: 30564623). Functional assessments of this variant are not available in the literature. R79C has been observed in population frequency databases (gnomAD: EAS 0.19%). In summary, there is insufficient evidence to classify NM_000231.2(SGCG):c.235C>T(R79C) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

Feb 06, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:3

Dec 27, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2017

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 28, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29089047) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.96

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.23

MetaSVM

Pathogenic

0.99

MutationAssessor

Uncertain

2.7

PhyloP100

3.5

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.53

MVP

0.99

MPC

0.44

ClinPred

0.092

GERP RS

5.5

Varity_R

0.63

gMVP

0.77

Mutation Taster

=45/55

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over