rs752000538

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3BS1_Supporting

The NM_000337.6(SGCD):c.458A>G(p.Asp153Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000363 in 1,460,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

SGCD
NM_000337.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.65

Publications

0 publications found

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 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 2F
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, Ambry Genetics
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
dilated cardiomyopathy
Inheritance: AD Classification: LIMITED Submitted by: ClinGen
dilated cardiomyopathy 1L
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

SGCD links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.819

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000363 (53/1460180) while in subpopulation AMR AF = 0.00114 (51/44572). AF 95% confidence interval is 0.000893. There are 0 homozygotes in GnomAdExome4. There are 27 alleles in the male GnomAdExome4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCD	NM_000337.6 link	c.458A>G	p.Asp153Gly	missense_variant	Exon 6 of 9	ENST00000337851.9	NP_000328.2	Q92629-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SGCD	ENST00000337851.9 link	c.458A>G	p.Asp153Gly	missense_variant	Exon 6 of 9	1	NM_000337.6	ENSP00000338343.4	Q92629-2
SGCD	ENST00000435422.7 link	c.455A>G	p.Asp152Gly	missense_variant	Exon 5 of 8	1		ENSP00000403003.2	Q92629-1
SGCD	ENST00000517913.5 link	c.458A>G	p.Asp153Gly	missense_variant	Exon 8 of 10	5		ENSP00000429378.1	Q92629-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000182

AC:

AN:

247856

AF XY:

0.000171

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00126

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000890

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1460180

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

726404

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33438

American (AMR)

AF:

0.00114

AC:

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26092

East Asian (EAS)

AF:

0.00

AC:

AN:

39664

South Asian (SAS)

AF:

0.00

AC:

AN:

86124

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110842

Other (OTH)

AF:

0.0000166

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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

Cov.:

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.000117

ExAC

AF:

0.000149

AC:

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 2F

Uncertain:2

Feb 08, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 153 of the SGCD protein (p.Asp153Gly). This variant is present in population databases (rs752000538, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with SGCD-related conditions. ClinVar contains an entry for this variant (Variation ID: 411706). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SGCD protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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. -

not provided

Uncertain:2

Feb 03, 2021

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 411706; Landrum et al., 2016) -

Dec 28, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Jan 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D153G variant (also known as c.458A>G), located in coding exon 5 of the SGCD gene, results from an A to G substitution at nucleotide position 458. The aspartic acid at codon 153 is replaced by glycine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Autosomal recessive limb-girdle muscular dystrophy type 2F;C1847667:Dilated cardiomyopathy 1L

Uncertain:1

Sep 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dilated cardiomyopathy 1L

Uncertain:1

Feb 08, 2023

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

.;D;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.82

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.1

.;M;.

PhyloP100

6.7

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-5.6

D;D;D

REVEL

Pathogenic

0.90

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

1.0

D;P;P

Vest4

0.94

MutPred

0.67

.;Loss of stability (P = 0.0351);.;

MVP

0.99

MPC

0.37

ClinPred

0.66

GERP RS

5.7

Varity_R

0.68

gMVP

0.75

Mutation Taster

=21/79

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over