13-23324525-A-G

Position:

chr13-23324525-A-G

Variant summary

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

The NM_000231.3(SGCG):c.860A>G(p.Asn287Ser) variant causes a missense change. The variant allele was found at a frequency of 0.873 in 1,611,402 control chromosomes in the GnomAD database, including 615,354 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.84 ( 54415 hom., cov: 29)

Exomes 𝑓: 0.88 ( 560939 hom. )

Consequence

SGCG
NM_000231.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 4.11

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:

SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

SACS 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 28 pathogenic changes around while only 1 benign (97%) in NM_000231.3

BP4

Computational evidence support a benign effect (MetaRNN=6.4305704E-7).

BP6

Variant 13-23324525-A-G is Benign according to our data. Variant chr13-23324525-A-G is described in ClinVar as [Benign]. Clinvar id is 167681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23324525-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 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.860A>G	p.Asn287Ser	missense_variant	8/8	ENST00000218867.4	NP_000222.2	Q13326

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCG	ENST00000218867.4 linkuse as main transcript	c.860A>G	p.Asn287Ser	missense_variant	8/8	1	NM_000231.3	ENSP00000218867.3		Q13326

Frequencies

GnomAD3 genomes

AF:

0.843

AC:

128032

AN:

151806

Hom.:

54383

Cov.:

show subpopulations

Gnomad AFR

AF:

0.740

Gnomad AMI

AF:

0.836

Gnomad AMR

AF:

0.899

Gnomad ASJ

AF:

0.916

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.920

Gnomad FIN

AF:

0.890

Gnomad MID

AF:

0.801

Gnomad NFE

AF:

0.865

Gnomad OTH

AF:

0.865

GnomAD3 exomes

AF:

0.886

AC:

222275

AN:

250754

Hom.:

98962

AF XY:

0.888

AC XY:

120406

AN XY:

135572

show subpopulations

Gnomad AFR exome

AF:

0.739

Gnomad AMR exome

AF:

0.935

Gnomad ASJ exome

AF:

0.916

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.913

Gnomad FIN exome

AF:

0.883

Gnomad NFE exome

AF:

0.866

Gnomad OTH exome

AF:

0.883

GnomAD4 exome

AF:

0.876

AC:

1278246

AN:

1459478

Hom.:

560939

Cov.:

AF XY:

0.877

AC XY:

636522

AN XY:

726134

show subpopulations

Gnomad4 AFR exome

AF:

0.732

Gnomad4 AMR exome

AF:

0.931

Gnomad4 ASJ exome

AF:

0.918

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.912

Gnomad4 FIN exome

AF:

0.882

Gnomad4 NFE exome

AF:

0.870

Gnomad4 OTH exome

AF:

0.877

GnomAD4 genome

AF:

0.843

AC:

128121

AN:

151924

Hom.:

54415

Cov.:

AF XY:

0.849

AC XY:

63055

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.740

Gnomad4 AMR

AF:

0.899

Gnomad4 ASJ

AF:

0.916

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.921

Gnomad4 FIN

AF:

0.890

Gnomad4 NFE

AF:

0.865

Gnomad4 OTH

AF:

0.867

Alfa

AF:

0.868

Hom.:

93145

Bravo

AF:

0.842

TwinsUK

AF:

0.866

AC:

3212

ALSPAC

AF:

0.876

AC:

3375

ESP6500AA

AF:

0.731

AC:

3221

ESP6500EA

AF:

0.867

AC:

7458

ExAC

AF:

0.882

AC:

107033

Asia WGS

AF:

0.944

AC:

3283

AN:

3478

EpiCase

AF:

0.861

EpiControl

AF:

0.864

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 29, 2013	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	This is a RefSeq error. The reference base (c.860A) is the minor allele. This al lele (A) has been identified in 13% (1142/8600) of European American chromosomes and 27% (1185/4406) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1800354) and thus meets c riteria to be classified as benign. -
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	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 16, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Charlevoix-Saguenay spastic ataxia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.045

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.57

DEOGEN2

Benign

0.24

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.18

MetaRNN

Benign

6.4e-7

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-2.2

PrimateAI

Benign

0.45

PROVEAN

Benign

0.86

REVEL

Benign

0.22

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.018

MPC

0.056

ClinPred

0.0020

GERP RS

5.4

Varity_R

0.038

gMVP

0.45

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