rs190935424

Variant names:

• chr5-156594951-T-C
• rs190935424
• NM_000337.6:c.402T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-156594951-T-C
• chr5-156594951-T-A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_000337.6(SGCD):​c.402T>C​(p.Ala134Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000677 in 1,609,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: SGCD NM_000337.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 0.122
• Publications: 0 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 5-156594951-T-C is Benign according to our data. Variant chr5-156594951-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 202084.
• BP7: Synonymous conserved (PhyloP=0.122 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000112 (17/152214) while in subpopulation EAS AF = 0.0027 (14/5176). AF 95% confidence interval is 0.00164. There are 0 homozygotes in GnomAd4. There are 7 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.402T>C	p.Ala134Ala	synonymous	Exon 6 of 9	NP_000328.2
	SGCD	NM_001128209.2		c.399T>C	p.Ala133Ala	synonymous	Exon 5 of 8	NP_001121681.1	Q92629-1
	SGCD	NM_172244.3		c.402T>C	p.Ala134Ala	synonymous	Exon 6 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.402T>C	p.Ala134Ala	synonymous	Exon 6 of 9	ENSP00000338343.4	Q92629-2
	SGCD	ENST00000435422.7	TSL:1	c.399T>C	p.Ala133Ala	synonymous	Exon 5 of 8	ENSP00000403003.2	Q92629-1
	SGCD	ENST00000959784.1		c.453T>C	p.Ala151Ala	synonymous	Exon 7 of 10	ENSP00000629843.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000200 AC: 49 AN: 245088 AF XY: 0.000166

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.0000587

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00237

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000631 AC: 92 AN: 1457496 Hom.: 0 Cov.: 29 AF XY: 0.0000635 AC XY: 46 AN XY: 724938

African (AFR) AF: 0.0000299 AC: 1 AN: 33402

American (AMR) AF: 0.0000450 AC: 2 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00139 AC: 55 AN: 39656

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85718

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109110

Other (OTH) AF: 0.000332 AC: 20 AN: 60210

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74416

African (AFR) AF: 0.0000241 AC: 1 AN: 41542

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00270 AC: 14 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68008

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.0000789 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	1	1	not provided (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2F (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	4.7
DANN	Benign	0.61
PhyloP100		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs190935424; hg19: chr5-156021961;