rs180898690

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

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. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

SGCD
NM_172244.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:7

Conservation

PhyloP100: -0.469

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a topological_domain Extracellular (size 232) in uniprot entity SGCD_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_172244.3

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 id is 48123.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, Uncertain_significance=1}.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCD	NM_000337.6 link	c.699+18C>G		intron_variant	Intron 8 of 8	ENST00000337851.9	NP_000328.2	Q92629-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SGCD	ENST00000337851.9 link	c.699+18C>G		intron_variant	Intron 8 of 8	1	NM_000337.6	ENSP00000338343.4	Q92629-2
SGCD	ENST00000435422.7 link	c.696+18C>G		intron_variant	Intron 7 of 7	1		ENSP00000403003.2	Q92629-1
SGCD	ENST00000517913.5 link	c.717C>G	p.Asp239Glu	missense_variant	Exon 10 of 10	5		ENSP00000429378.1	Q92629-3

Frequencies

GnomAD3 genomes

AF:

0.000302

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.000852

AC:

187

AN:

219612

Hom.:

AF XY:

0.000849

AC XY:

100

AN XY:

117812

show subpopulations

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 SAS exome

AF:

0.0000373

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.:

Cov.:

AF XY:

0.000215

AC XY:

154

AN XY:

716322

show subpopulations

Gnomad4 AFR exome

AF:

0.0000905

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00702

Gnomad4 SAS exome

AF:

0.0000241

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000272

Gnomad4 OTH exome

AF:

0.000484

GnomAD4 genome

AF:

0.000302

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00713

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000188

Hom.:

Bravo

AF:

0.000385

ExAC

AF:

0.000572

AC:

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:2

Jun 02, 2014

Stanford Center for Inherited Cardiovascular Disease, Stanford University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. IVS12+1 G>A (c.2489+1 G>A) in the PKP2 gene This is a variant that we can have high confidence causes ARVC. It has been reported previously in multiple patients with ARVC, from multiple ethnicities, and also in multiple unrelated individuals tested for ARVC at the testing laboratory, according to their report. It is a splice-site variant that destroys the canonical splice donor site in intron 12. It is expected to cause abnormal gene splicing, which may lead to protein truncation or absence of protein due to mRNA decay. At least 24 patients with this specific variant have been published in the literature. Gerull et al. (2004) identified it in 1 ARVC proband of Western European descent. Dalal et al. (2006) found it in 3 unrelated patients with ARVC from the Johns Hopkins registry– and den Haan et al. (2009) added 1 more North American patient to this group. Age at first symptom for these patients ranged from 22-51 years. [Reports by Dalal et al. (2009) and Tan et al. (2010) appear to refer to these same patients.] van Tintelen et al. (2006) found the variant in 3 unrelated Dutch Caucasian individuals with ARVC. Of the cohort studied, patients with this variant had the youngest age of onset (ages 17, 17, and 20). Haplotype analysis indicated that it may be a founder mutation. One patient also carried a missense variant in PKP2: p.Glu62Lys. [Bhuiyan et al. (2009) appears to refer to the same patients as the van Tintelen et al. study.] Cox et al. 2011 identified it in 6 index patients (it is unclear how many of these were in the prior paper by van Tintelen et al. 2006 from the same group); two patients also carried a missense variant in DSG2 or JUP. Two 16-year-old males in one of these families suffered sudden cardiac death. Wlodarska et al. 2008 saw it in at least one Polish patient. Fressart et al. (2010) found it in 3 unrelated individuals recruited in France and/or Switzerland. Quarta et al. (2011) saw it in one patient referred to a center in London. Palmisano et al. (2011) studied a young male athlete with aborted cardiac arrest at age 21 and his affected but asymptomatic father, who both carried this variant and also a DSC2 I109M variant. The family’s ancestry may have been from Iran. Nakajima et al. (2012) found the variant in a Japanese patient who also carried the PKP2 variant D812N (in trans, one inherited from each of his unaffected parents). He had his first cardiac syncopal event (VT) at age 11 and was diagnosed at age 20. Baskin et al. (2013) found the variant in 2 ARVC patients tested in Canada. Bao et al. (2013) found it in 4 Chinese patients with ARVC. There is only very weak segregation data available: van Tintelen et al. (2006) saw it segregate in 2 affected family members. Palmisano et al. (2011) saw it segregate in an affected father and son. In total the variant has not been seen in more than 8500 presumably unaffected individuals, including 2000 controls and ~6500 individuals from population datasets. Dalal et al. (2006) did not find it in 200 controls (ancestry not specified); van Tintelen et al. (2006), 150 Caucasian controls; Wlodarska et al. (2008), 100 Caucasian controls; Fressart et al. (2010), 300 Caucasian controls; Cox et al. (2011), 200 Dutch Caucasian controls; Quarta et al. (2011), 300 ethnically-matched controls; Nakajima et al. (2012), 80 Japanese controls; Baskin et al. (2013), 427 controls; Bao et al. (2013), 300 Chinese(?) controls. It is not seen in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4300 Caucasian and ~2200 African American individuals. None of these individuals are ancestry-matched to our patient, whose ancestry is Chinese. The -

Nov 03, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 06, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Asp239Glu in exon 8 of SGCD: This variant is not expected to have clinical sig nificance because has been reported in multiple Asian individuals with various c ardiomyopathies and did not segregate with disease in 2 affected relatives in on e family. In addition, it has been identified in 0.3% (2/572) of Asian chromosom es by the 1000 Genomes Project (dbSNP rs180898690) and in 1.5% (54/3652) East As ian chromosomes by the Exome Aggregation Consortium (ExAC; http://exac.broadinst itute.org). -

not provided

Uncertain:1Benign:2

Jun 24, 2013

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

Sep 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 27, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

SGCD-related disorder

Benign:1

Aug 20, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal recessive limb-girdle muscular dystrophy type 2F

Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2F;C1847667:Dilated cardiomyopathy 1L

Benign:1

Nov 19, 2017

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.69

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

LIST_S2

Benign

0.20

MetaRNN

Benign

0.0048

MetaSVM

Benign

-1.0

PROVEAN

Benign

0.19

REVEL

Benign

0.068

Sift

Benign

0.059

Sift4G

Benign

0.12

Polyphen

0.0080

Vest4

0.076

MutPred

0.24

Gain of sheet (P = 0.0221);

MVP

0.54

ClinPred

0.0080

GERP RS

2.3

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over