chr5-156117876-A-G

Variant names:

• chr5-156117876-A-G
• rs183172007
• ENST00000517913.5:c.-281-2A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BS1 BS2

The ENST00000517913.5(SGCD):​c.-281-2A>G variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00677 in 152,250 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGCD ENST00000517913.5 splice_acceptor, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.33
• Publications: 1 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• BP6: Variant 5-156117876-A-G is Benign according to our data. Variant chr5-156117876-A-G is described in ClinVar as [Benign]. Clinvar id is 1695144.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00677 (1030/152250) while in subpopulation NFE AF = 0.0107 (726/68018). AF 95% confidence interval is 0.01. There are 7 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCD	XM_017009724.2	c.-207-5980A>G		intron_variant	Intron 1 of 9		XP_016865213.1
SGCD	XM_047417518.1	c.-207-5980A>G		intron_variant	Intron 3 of 11		XP_047273474.1
SGCD	XM_047417519.1	c.-207-5980A>G		intron_variant	Intron 2 of 10		XP_047273475.1
SGCD	XM_047417520.1	c.-164-5980A>G		intron_variant	Intron 1 of 8		XP_047273476.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCD	ENST00000517913.5	c.-281-2A>G		splice_acceptor_variant, intron_variant	Intron 1 of 9	5		ENSP00000429378.1

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1031 AN: 152132 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00525

Gnomad ASJ AF: 0.00866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00998

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.00671

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 8 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

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

GnomAD4 genome AF: 0.00677 AC: 1030 AN: 152250 Hom.: 7 Cov.: 32 AF XY: 0.00661 AC XY: 492 AN XY: 74440

African (AFR) AF: 0.00166 AC: 69 AN: 41558

American (AMR) AF: 0.00524 AC: 80 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00866 AC: 30 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00998 AC: 106 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0107 AC: 726 AN: 68018

Other (OTH) AF: 0.00664 AC: 14 AN: 2108

Alfa AF: 0.00858 Hom.: 0

Bravo AF: 0.00625

Asia WGS AF: 0.000866 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SGCD: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	9.1
DANN	Benign	0.37
PhyloP100		-1.3
Mutation Taster		=95/5	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs183172007; hg19: chr5-155544886;