rs80086857

Positions:

• chr5-156759198-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000337.6(SGCD):​c.700-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 1,607,908 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (91 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (94 hom.)
• Consequence: SGCD NM_000337.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.22

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 5-156759198-T-C is Benign according to our data. Variant chr5-156759198-T-C is described in ClinVar as [Benign]. Clinvar id is 255871.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-156759198-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0672 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCD	NM_000337.6	c.700-19T>C		intron_variant		ENST00000337851.9	NP_000328.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCD	ENST00000337851.9	c.700-19T>C		intron_variant		1	NM_000337.6	ENSP00000338343.4
SGCD	ENST00000435422.7	c.697-19T>C		intron_variant		1		ENSP00000403003.2

Frequencies

GnomAD3 genomes AF: 0.0204 AC: 3101 AN: 152164 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0691

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0144

GnomAD3 exomes AF: 0.00499 AC: 1237 AN: 248096 Hom.: 40 AF XY: 0.00360 AC XY: 485 AN XY: 134716

Gnomad AFR exome AF: 0.0678

Gnomad AMR exome AF: 0.00407

Gnomad ASJ exome AF: 0.0000995

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000178

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00188 AC: 2741 AN: 1455626 Hom.: 94 Cov.: 28 AF XY: 0.00158 AC XY: 1145 AN XY: 724522

Gnomad4 AFR exome AF: 0.0655

Gnomad4 AMR exome AF: 0.00461

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000687

Gnomad4 OTH exome AF: 0.00426

GnomAD4 genome AF: 0.0205 AC: 3116 AN: 152282 Hom.: 91 Cov.: 32 AF XY: 0.0198 AC XY: 1475 AN XY: 74452

Gnomad4 AFR AF: 0.0693

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.0142

Alfa AF: 0.0123 Hom.: 8

Bravo AF: 0.0235

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 18, 2019	Variant summary: SGCD c.700-19T>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.005 in 248096 control chromosomes, predominantly at a frequency of 0.068 within the African or African-American subpopulation in the gnomAD database, including 39 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2720-fold the estimated maximal pathogenic allele frequency expected for a variant in SGCD causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.700-19T>C in individuals affected with Cardiomyopathy and no experimental evidence demonstrating an impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and cited the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Dilated cardiomyopathy 1L Benign:1

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	-0.41
CADD	Benign	17
DANN	Benign	0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs80086857; hg19: chr5-156186209;