ENST00000435422.7:c.-329C>G

Variant names:

• chr5-156326904-C-G
• rs7717393
• ENST00000435422.7:c.-329C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The ENST00000435422.7(SGCD):​c.-329C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0759 in 152,334 control chromosomes in the GnomAD database, including 454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.076 (454 hom., cov: 33)
  • Exomes 𝑓: 0.10 (0 hom.)
• Consequence: SGCD ENST00000435422.7 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.50
• Publications: 8 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 Submitted by: ClinGen
• autosomal recessive limb-girdle muscular dystrophy type 2F

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health, Ambry Genetics
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• dilated cardiomyopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• dilated cardiomyopathy 1L

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

LOC124901120 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-156326904-C-G is Benign according to our data. Variant chr5-156326904-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48112.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=2}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCD	XM_017009724.2	c.-43-2630C>G		intron_variant	Intron 2 of 9		XP_016865213.1
SGCD	XM_047417518.1	c.-43-2630C>G		intron_variant	Intron 4 of 11		XP_047273474.1
SGCD	XM_047417519.1	c.-43-2630C>G		intron_variant	Intron 3 of 10		XP_047273475.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCD	ENST00000435422.7	c.-329C>G		5_prime_UTR_variant	Exon 1 of 8	1		ENSP00000403003.2
SGCD	ENST00000517913.5	c.-43-2630C>G		intron_variant	Intron 3 of 9	5		ENSP00000429378.1
SGCD	ENST00000524347.2	n.-372C>G		upstream_gene_variant		5		ENSP00000430794.1

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11528 AN: 152146 Hom.: 454 Cov.: 33

Gnomad AFR AF: 0.0783

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.0808

Gnomad ASJ AF: 0.0836

Gnomad EAS AF: 0.0469

Gnomad SAS AF: 0.186

Gnomad FIN AF: 0.0449

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0717

Gnomad OTH AF: 0.0836

GnomAD4 exome AF: 0.100 AC: 7 AN: 70 Hom.: 0 Cov.: 0 AF XY: 0.0962 AC XY: 5 AN XY: 52

African (AFR) AF: 0.250 AC: 1 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.103 AC: 6 AN: 58

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0759 AC: 11552 AN: 152264 Hom.: 454 Cov.: 33 AF XY: 0.0773 AC XY: 5758 AN XY: 74454

African (AFR) AF: 0.0782 AC: 3249 AN: 41532

American (AMR) AF: 0.0816 AC: 1249 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0836 AC: 290 AN: 3468

East Asian (EAS) AF: 0.0472 AC: 244 AN: 5174

South Asian (SAS) AF: 0.188 AC: 906 AN: 4828

European-Finnish (FIN) AF: 0.0449 AC: 476 AN: 10612

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0717 AC: 4878 AN: 68028

Other (OTH) AF: 0.0827 AC: 175 AN: 2116

Alfa AF: 0.0334 Hom.: 15

Bravo AF: 0.0761

Asia WGS AF: 0.116 AC: 404 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Qualitative or quantitative defects of delta-sarcoglycan Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Apr 20, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.30
DANN	Benign	0.73
PhyloP100		-1.5
PromoterAI		-0.025	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs7717393; hg19: chr5-155753914;