rs11748588

chr5-156508710-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000337.6(SGCD):c.294+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00663 in 1,505,194 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0061 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (41 hom.)
• Consequence: SGCD NM_000337.6 splice_region, intron
• Scores: Splicing: ADA: 0.00008836
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.104

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-156508710-T-C is Benign according to our data. Variant chr5-156508710-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 36772.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-156508710-T-C is described in Lovd as [Benign]. Variant chr5-156508710-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00612 (932/152314) while in subpopulation NFE AF= 0.00788 (536/68022). AF 95% confidence interval is 0.00733. There are 3 homozygotes in gnomad4. There are 504 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCD	NM_000337.6	c.294+8T>C		splice_region_variant, intron_variant		ENST00000337851.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCD	ENST00000337851.9	c.294+8T>C		splice_region_variant, intron_variant		1	NM_000337.6	P4
SGCD	ENST00000435422.7	c.291+8T>C		splice_region_variant, intron_variant		1		A1
SGCD	ENST00000517913.5	c.294+8T>C		splice_region_variant, intron_variant		5
SGCD	ENST00000524347.2	c.*158+8T>C		splice_region_variant, intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00612 AC: 932 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.0136

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0207

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00788

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00663 AC: 1540 AN: 232398 Hom.: 6 AF XY: 0.00674 AC XY: 850 AN XY: 126102

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.00322

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00238

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.00758

Gnomad OTH exome AF: 0.00898

GnomAD4 exome AF: 0.00668 AC: 9042 AN: 1352880 Hom.: 41 Cov.: 20 AF XY: 0.00658 AC XY: 4455 AN XY: 677194

Gnomad4 AFR exome AF: 0.000878

Gnomad4 AMR exome AF: 0.00340

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00223

Gnomad4 FIN exome AF: 0.0176

Gnomad4 NFE exome AF: 0.00701

Gnomad4 OTH exome AF: 0.00525

GnomAD4 genome AF: 0.00612 AC: 932 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00677 AC XY: 504 AN XY: 74484

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.0136

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0207

Gnomad4 NFE AF: 0.00788

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00712 Hom.: 2

Bravo AF: 0.00504

Asia WGS AF: 0.00260 AC: 10 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 28, 2009	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 12, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 26, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SGCD: BP4, BS2 -

Autosomal recessive limb-girdle muscular dystrophy type 2F Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -

Cardiomyopathy Benign:2

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 22, 2010	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 01, 2016	- -

Qualitative or quantitative defects of delta-sarcoglycan Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Limb-Girdle Muscular Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Dilated cardiomyopathy 1L Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Feb 08, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	11
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000088
dbscSNV1_RF	Benign	0.0
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

Publications

LitVar

Other links and lift over

dbSNP: rs11748588; hg19: chr5-155935720;