NM_000337.6:c.848A>G

Variant names:

• chr5-156759365-A-G
• rs397516338
• NM_000337.6:c.848A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 8.82
• Publications: 11 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• 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 VariationId is 43358.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.848A>G	p.Gln283Arg	missense	Exon 9 of 9	NP_000328.2
	SGCD	NM_001128209.2		c.845A>G	p.Gln282Arg	missense	Exon 8 of 8	NP_001121681.1	Q92629-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCD	ENST00000337851.9	TSL:1 MANE Select	c.848A>G	p.Gln283Arg	missense	Exon 9 of 9	ENSP00000338343.4	Q92629-2
	SGCD	ENST00000435422.7	TSL:1	c.845A>G	p.Gln282Arg	missense	Exon 8 of 8	ENSP00000403003.2	Q92629-1
	SGCD	ENST00000959784.1		c.899A>G	p.Gln300Arg	missense	Exon 10 of 10	ENSP00000629843.1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152146 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000556 AC: 138 AN: 248152 AF XY: 0.000475

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 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.: 1 Cov.: 30 AF XY: 0.000159 AC XY: 115 AN XY: 725344

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.0000224 AC: 1 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00578 AC: 229 AN: 39644

South Asian (SAS) AF: 0.0000813 AC: 7 AN: 86102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5730

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109622

Other (OTH) AF: 0.000265 AC: 16 AN: 60266

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74450

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00541 AC: 28 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.000404

ExAC AF: 0.000463 AC: 56

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	-	2	not specified (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2F (1)
-	-	1	Hypertrophic cardiomyopathy 1 (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Qualitative or quantitative defects of delta-sarcoglycan (1)
-	-	1	SGCD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		8.8
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.5	N
REVEL	Pathogenic	0.86
Sift	Benign	0.059	T
Sift4G	Benign	0.37	T
Polyphen		0.98	D
Vest4		0.56
MutPred		0.63		Gain of sheet (P = 0.1945)
MVP		0.93
MPC		0.15
ClinPred		0.25	T
GERP RS		4.9
Varity_R		0.34
gMVP		0.52
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

dbSNP: rs397516338; hg19: chr5-156186376;