chr5-156344576-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_SupportingPP3

This summary comes from the ClinGen Evidence Repository: The NM_000337.6: c.91C>G variant in SGCD is a missense variant predicted to cause substitution of arginine by glycine at amino acid 31 (p.Arg31Gly). This variant is absent from gnomAD v2.1.1 and v4.1.0 genomes (note that the variant fails filter in exome data, suggesting it may be a sequencing artifact) (PM2_Supporting). The computational predictor REVEL gives a score of 0.85, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCD function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM2_Supporting, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA200046/MONDO:0015152/186

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SGCD
NM_000337.6 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:1B:1

Conservation

PhyloP100: 1.52

Publications

3 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:

LOC124901120 (HGNC:):

LOC124901120 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCD	NM_000337.6 link	c.91C>G	p.Arg31Gly	missense_variant	Exon 3 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.91C>G	p.Arg31Gly	missense_variant	Exon 3 of 9	1	NM_000337.6	ENSP00000338343.4	Q92629-2
SGCD	ENST00000435422.7 link	c.88C>G	p.Arg30Gly	missense_variant	Exon 2 of 8	1		ENSP00000403003.2	Q92629-1
SGCD	ENST00000517913.5 link	c.91C>G	p.Arg31Gly	missense_variant	Exon 5 of 10	5		ENSP00000429378.1	Q92629-3
SGCD	ENST00000524347.2 link	n.91C>G		non_coding_transcript_exon_variant	Exon 3 of 6	5		ENSP00000430794.1	E5RI34

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.000803

AC:

194

AN:

241742

AF XY:

0.000521

show subpopulations

Gnomad AFR exome

AF:

0.00392

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000303

Gnomad EAS exome

AF:

0.000169

Gnomad FIN exome

AF:

0.000618

Gnomad NFE exome

AF:

0.00106

Gnomad OTH exome

AF:

0.000690

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000473

AC:

AN:

1457452

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

724996

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

44436

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.000101

AC:

AN:

39530

South Asian (SAS)

AF:

0.00

AC:

AN:

85836

European-Finnish (FIN)

AF:

0.000906

AC:

AN:

51898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000135

AC:

AN:

1110436

Other (OTH)

AF:

0.0000499

AC:

AN:

60084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.276

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.:

ExAC

AF:

0.0139

AC:

1679

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy

Uncertain:1

Jan 08, 2025

ClinGen Limb Girdle Muscular Dystrophy Variant Curation Expert Panel, ClinGen

Significance:Uncertain significance

Review Status:reviewed by expert panel

Collection Method:curation

The NM_000337.6: c.91C>G variant in SGCD is a missense variant predicted to cause substitution of arginine by glycine at amino acid 31 (p.Arg31Gly). This variant is absent from gnomAD v2.1.1 and v4.1.0 genomes (note that the variant fails filter in exome data, suggesting it may be a sequencing artifact) (PM2_Supporting). The computational predictor REVEL gives a score of 0.85, which is above the threshold of ≥0.70, evidence that correlates with impact to SGCD function (PP3). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal recessive limb girdle muscular dystrophy based on the ACMG/AMP criteria applied, as specified by the ClinGen LGMD VCEP (LGMD VCEP specifications version 1.0.0; 01/08/2025): PM2_Supporting, PP3. -

not specified

Benign:1

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.98

.;D;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.89

D;D;D

MetaRNN

Benign

0.016

T;T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.6

.;M;.

PhyloP100

1.5

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-6.4

D;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;P;P

Vest4

0.24

MPC

0.65

ClinPred

0.047

GERP RS

1.6

Varity_R

0.76

gMVP

0.90

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.32

Position offset: -28

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