rs180898690

Variant names:

• chr5-156757722-C-G
• rs180898690
• NM_000337.6:c.699+18C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-156757722-C-G
• chr5-156757722-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_172244.3(SGCD):​c.717C>G​(p.Asp239Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000224 in 1,596,596 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D239N) has been classified as Likely benign. The gene SGCD is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: SGCD NM_172244.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8
• Conservation: PhyloP100: -0.469
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048123).
• BP6: Variant 5-156757722-C-G is Benign according to our data. Variant chr5-156757722-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 48123.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000302 (46/152202) while in subpopulation EAS AF = 0.00713 (37/5186). AF 95% confidence interval is 0.00532. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_172244.3. 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.699+18C>G		intron	N/A	NP_000328.2
	SGCD	NM_172244.3		c.717C>G	p.Asp239Glu	missense	Exon 8 of 8	NP_758447.1	Q92629-3
	SGCD	NM_001128209.2		c.696+18C>G		intron	N/A	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.699+18C>G		intron	N/A	ENSP00000338343.4	Q92629-2
	SGCD	ENST00000435422.7	TSL:1	c.696+18C>G		intron	N/A	ENSP00000403003.2	Q92629-1
	SGCD	ENST00000517913.5	TSL:5	c.717C>G	p.Asp239Glu	missense	Exon 10 of 10	ENSP00000429378.1	Q92629-3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000852 AC: 187 AN: 219612 AF XY: 0.000849

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0113

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000726

GnomAD4 exome AF: 0.000216 AC: 312 AN: 1444394 Hom.: 2 Cov.: 31 AF XY: 0.000215 AC XY: 154 AN XY: 716322

African (AFR) AF: 0.0000905 AC: 3 AN: 33140

American (AMR) AF: 0.00 AC: 0 AN: 41840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25718

East Asian (EAS) AF: 0.00702 AC: 275 AN: 39172

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 82910

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52518

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

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1103482

Other (OTH) AF: 0.000484 AC: 29 AN: 59866

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74430

African (AFR) AF: 0.000144 AC: 6 AN: 41524

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00713 AC: 37 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000188 Hom.: 0

Bravo AF: 0.000385

ExAC AF: 0.000572 AC: 69

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	1	2	not provided (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2F (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2F;C1847667:Dilated cardiomyopathy 1L (1)
-	-	1	SGCD-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.9
DANN	Benign	0.15
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.065	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.47
PROVEAN	Benign	0.19	N
REVEL	Benign	0.068
Sift	Benign	0.059	T
Sift4G	Benign	0.12	T
Polyphen		0.0080	B
Vest4		0.076
MutPred		0.24		Gain of sheet (P = 0.0221)
MVP		0.54
ClinPred		0.0080	T
GERP RS		2.3
Mutation Taster		=98/2	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: rs180898690; hg19: chr5-156184733; COSMIC: COSV107429019;