chr5-156344576-C-G

Variant names:

• chr5-156344576-C-G
• rs202223676
• NM_000337.6:c.91C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2_Supporting PP3

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
• Clinical Significance: Uncertain significance reviewed by expert panel U:1 B:1
• Conservation: PhyloP100: 1.52
• Publications: 3 publications found

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, STRONG Submitted by: ClinGen, PanelApp Australia
• autosomal recessive limb-girdle muscular dystrophy type 2F

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• dilated cardiomyopathy 1L

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

LOC124901120 (HGNC:):

ACMG classification

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000337.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	NM_000337.6	MANE Select	c.91C>G	p.Arg31Gly	missense	Exon 3 of 9	NP_000328.2
	SGCD	NM_001128209.2		c.88C>G	p.Arg30Gly	missense	Exon 2 of 8	NP_001121681.1	Q92629-1
	SGCD	NM_172244.3		c.91C>G	p.Arg31Gly	missense	Exon 3 of 8	NP_758447.1	Q92629-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	ENST00000337851.9	TSL:1 MANE Select	c.91C>G	p.Arg31Gly	missense	Exon 3 of 9	ENSP00000338343.4	Q92629-2
	SGCD	ENST00000435422.7	TSL:1	c.88C>G	p.Arg30Gly	missense	Exon 2 of 8	ENSP00000403003.2	Q92629-1
	SGCD	ENST00000959784.1		c.91C>G	p.Arg31Gly	missense	Exon 3 of 10	ENSP00000629843.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000803 AC: 194 AN: 241742 AF XY: 0.000521

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: 69 AN: 1457452 Hom.: 0 Cov.: 32 AF XY: 0.0000607 AC XY: 44 AN XY: 724996

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

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44436

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39530

South Asian (SAS) AF: 0.00 AC: 0 AN: 85836

European-Finnish (FIN) AF: 0.000906 AC: 47 AN: 51898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1110436

Other (OTH) AF: 0.0000499 AC: 3 AN: 60084

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.0139 AC: 1679

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive limb-girdle muscular dystrophy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.016	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.5
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.24
MPC		0.65
ClinPred		0.047	T
GERP RS		1.6
Varity_R		0.76
gMVP		0.90
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs202223676; hg19: chr5-155771586; COSMIC: COSV61905583;