rs74846539
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Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2
The NM_000337.6(SGCD):c.213G>A(p.Arg71=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,610,140 control chromosomes in the GnomAD database, including 4 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 0.0012 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0019 ( 3 hom. )
Consequence
SGCD
NM_000337.6 synonymous
NM_000337.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.52
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.43).
BP6
?
Variant 5-156508621-G-A is Benign according to our data. Variant chr5-156508621-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 48116.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Likely_benign=6, Uncertain_significance=2}. Variant chr5-156508621-G-A is described in Lovd as [Likely_benign].
BP7
?
Synonymous conserved (PhyloP=2.52 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0012 (183/152194) while in subpopulation NFE AF= 0.00212 (144/68002). AF 95% confidence interval is 0.00184. There are 1 homozygotes in gnomad4. There are 82 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SGCD | NM_000337.6 | c.213G>A | p.Arg71= | synonymous_variant | 4/9 | ENST00000337851.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SGCD | ENST00000337851.9 | c.213G>A | p.Arg71= | synonymous_variant | 4/9 | 1 | NM_000337.6 | P4 | |
SGCD | ENST00000435422.7 | c.210G>A | p.Arg70= | synonymous_variant | 3/8 | 1 | A1 | ||
SGCD | ENST00000517913.5 | c.213G>A | p.Arg71= | synonymous_variant | 6/10 | 5 | |||
SGCD | ENST00000524347.2 | c.*77G>A | 3_prime_UTR_variant, NMD_transcript_variant | 5/6 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00120 AC: 183AN: 152076Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.00119 AC: 296AN: 248064Hom.: 2 AF XY: 0.00126 AC XY: 169AN XY: 134512
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GnomAD4 exome AF: 0.00190 AC: 2764AN: 1457946Hom.: 3 Cov.: 29 AF XY: 0.00183 AC XY: 1325AN XY: 725508
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GnomAD4 genome ? AF: 0.00120 AC: 183AN: 152194Hom.: 1 Cov.: 32 AF XY: 0.00110 AC XY: 82AN XY: 74406
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:13
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:4
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 25, 2015 | - - |
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 16, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 03, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 18, 2015 | p.Arg71Arg in exon 4 of SGCD: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.15% (95/64128) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs74846539). - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 28, 2019 | Variant summary: SGCD c.213G>A alters a conserved nucleotide resulting in a synonymous change. 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 0.0012 in 248064 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 48 fold of the estimated maximal expected allele frequency for a pathogenic variant in SGCD causing Cardiomyopathy phenotype (2.5e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.213G>A in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, four of whom classified the variant as likely benign and one as a VUS. Based on the evidence outlined above, the variant was classified as benign. - |
Qualitative or quantitative defects of delta-sarcoglycan Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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, 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. - |
Autosomal recessive limb-girdle muscular dystrophy type 2F Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 27, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Limb-girdle muscular dystrophy, recessive Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 04, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at