rs397516338

Positions:

chr5-156759365-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_000337.6(SGCD):c.848A>G(p.Gln283Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000179 in 1,611,148 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

SGCD
NM_000337.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: 8.82

Variant links:

Genes affected

SGCD (HGNC:10807): (sarcoglycan delta) The protein encoded by this gene is one of the four known components of the sarcoglycan complex, which is a subcomplex of the dystrophin-glycoprotein complex (DGC). DGC forms a link between the F-actin cytoskeleton and the extracellular matrix. This protein is expressed most abundantly in skeletal and cardiac muscle. Mutations in this gene have been associated with autosomal recessive limb-girdle muscular dystrophy and dilated cardiomyopathy. Alternatively spliced transcript variants encoding distinct isoforms have been observed for this gene. [provided by RefSeq, Jul 2008]

SGCD links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.021871299).

BP6

Variant 5-156759365-A-G is Benign according to our data. Variant chr5-156759365-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43358.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=2}. Variant chr5-156759365-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000197 (30/152264) while in subpopulation EAS AF= 0.00541 (28/5180). AF 95% confidence interval is 0.00384. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCD	NM_000337.6 linkuse as main transcript	c.848A>G	p.Gln283Arg	missense_variant	9/9	ENST00000337851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCD	ENST00000337851.9 linkuse as main transcript	c.848A>G	p.Gln283Arg	missense_variant	9/9	1	NM_000337.6	P4	Q92629-2
SGCD	ENST00000435422.7 linkuse as main transcript	c.845A>G	p.Gln282Arg	missense_variant	8/8	1		A1	Q92629-1

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00539

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000556

AC:

138

AN:

248152

Hom.:

AF XY:

0.000475

AC XY:

AN XY:

134624

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00757

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000178

AC:

259

AN:

1458884

Hom.:

Cov.:

AF XY:

0.000159

AC XY:

115

AN XY:

725344

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00578

Gnomad4 SAS exome

AF:

0.0000813

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000541

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000197

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00541

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000178

Hom.:

Bravo

AF:

0.000404

ExAC

AF:

0.000463

AC:

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 32344918, 26720722, 23861362, 27707468) -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 25, 2014	p.Gln283Arg in exon 9 of SGCD: This variant is not expected to have clinical sig nificance because it has been identified in 0.6% (57/8734) of East Asian chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516338). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2022	Variant summary: SGCD c.848A>G (p.Gln283Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 248152 control chromosomes (gnomAD), predominantly at a frequency of 0.0076 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in SGCD causing Limb-Girdle Muscular Dystrophy, Autosomal Recessive phenotype (0.00072), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.848A>G in individuals affected with Limb-Girdle Muscular Dystrophy, Autosomal Recessive has been reported. One publication has found that the variant protein interacts with other SGC proteins in an identical manner as wild-type, although there is reduced cell surface expression of the complete SGC complex (Chen_2015). Five ClinVar submitters have assessed the variant since 2014: all five classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

SGCD-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 17, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive limb-girdle muscular dystrophy type 2F

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Qualitative or quantitative defects of delta-sarcoglycan

Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Limb-girdle muscular dystrophy, recessive

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Primary dilated cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

research

Genetics and Genomics Program, Sidra Medicine

- -

Hypertrophic cardiomyopathy 1

Benign:1

Likely benign, criteria provided, single submitter

research

Agnes Ginges Centre for Molecular Cardiology, Centenary Institute

Mar 16, 2017

The SGCD Gln283Arg variant is present at high frequency in the Exome Aggregation Consortium dataset and is particularly common in the East Asian population; allele frequency=0.006379 (MAF= 0.0004690, http://exac.broadinstitute.org/). We identified SGCD Gln283Arg in 1 HCM proband with no family history of HCM or SCD. Computational tools PolyPhen-2 and MutationTaster predict the amino acid substitution to be "probably damaging" and "disease-causing" respectively, however SIFT predicts this variant to be "tolerated". In summary, based on the current literature, our limited understanding of the role of SGCD in HCM, and an allele frequency higher than expected for HCM, we classify SGCD Gln283Arg as "likely benign". -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.047

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.022

T;T

MetaSVM

Uncertain

0.74

MutationAssessor

Uncertain

2.2

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.5

N;N

REVEL

Pathogenic

0.86

Sift

Benign

0.059

T;T

Sift4G

Benign

0.37

T;T

Polyphen

0.98

D;D

Vest4

0.56

MutPred

0.63

Gain of sheet (P = 0.1945);.;

MVP

0.93

MPC

0.15

ClinPred

0.25

GERP RS

4.9

Varity_R

0.34

gMVP

0.52

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