rs74846539

Variant names:

• chr5-156508621-G-A
• rs74846539
• NM_000337.6:c.213G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000337.6(SGCD):​c.213G>A​(p.Arg71Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,610,140 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SGCD is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: SGCD NM_000337.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:15
• Conservation: PhyloP100: 2.52
• Publications: 4 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

Specifications for SGCD are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-156508621-G-A is Benign according to our data. Variant chr5-156508621-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48116.
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0012 (183/152194) while in subpopulation NFE AF = 0.00212 (144/68002). AF 95% confidence interval is 0.00184. There are 1 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.213G>A	p.Arg71Arg	synonymous	Exon 4 of 9	NP_000328.2
	SGCD	NM_001128209.2		c.210G>A	p.Arg70Arg	synonymous	Exon 3 of 8	NP_001121681.1	Q92629-1
	SGCD	NM_172244.3		c.213G>A	p.Arg71Arg	synonymous	Exon 4 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.213G>A	p.Arg71Arg	synonymous	Exon 4 of 9	ENSP00000338343.4	Q92629-2
	SGCD	ENST00000435422.7	TSL:1	c.210G>A	p.Arg70Arg	synonymous	Exon 3 of 8	ENSP00000403003.2	Q92629-1
	SGCD	ENST00000959784.1		c.264G>A	p.Arg88Arg	synonymous	Exon 5 of 10	ENSP00000629843.1

Frequencies

GnomAD3 genomes AF: 0.00120 AC: 183 AN: 152076 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00212

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00119 AC: 296 AN: 248064 AF XY: 0.00126

Gnomad AFR exome AF: 0.000453

Gnomad AMR exome AF: 0.000963

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00206

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00190 AC: 2764 AN: 1457946 Hom.: 3 Cov.: 29 AF XY: 0.00183 AC XY: 1325 AN XY: 725508

African (AFR) AF: 0.000270 AC: 9 AN: 33382

American (AMR) AF: 0.00101 AC: 45 AN: 44610

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39624

South Asian (SAS) AF: 0.000360 AC: 31 AN: 86042

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53376

Middle Eastern (MID) AF: 0.000695 AC: 4 AN: 5756

European-Non Finnish (NFE) AF: 0.00232 AC: 2576 AN: 1108826

Other (OTH) AF: 0.00163 AC: 98 AN: 60238

GnomAD4 genome AF: 0.00120 AC: 183 AN: 152194 Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74406

African (AFR) AF: 0.000482 AC: 20 AN: 41520

American (AMR) AF: 0.000981 AC: 15 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

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

European-Non Finnish (NFE) AF: 0.00212 AC: 144 AN: 68002

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00175 Hom.: 0

Bravo AF: 0.00125

EpiCase AF: 0.00131

EpiControl AF: 0.00167

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	5	not specified (5)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2F (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Qualitative or quantitative defects of delta-sarcoglycan (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	9.1
DANN	Benign	0.59
PhyloP100		2.5
Mutation Taster		=100/0	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: rs74846539; hg19: chr5-155935631;