rs1801191

chr17-50170328-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000023.4(SGCA):c.933C>T(p.Val311=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0469 in 1,613,718 control chromosomes in the GnomAD database, including 2,955 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.084 (935 hom., cov: 32)
  • Exomes 𝑓: 0.043 (2020 hom.)
• Consequence: SGCA NM_000023.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.90

Genes affected

SGCA (HGNC:10805): (sarcoglycan alpha) This gene encodes a component of the dystrophin-glycoprotein complex (DGC), which is critical to the stability of muscle fiber membranes and to the linking of the actin cytoskeleton to the extracellular matrix. Its expression is thought to be restricted to striated muscle. Mutations in this gene result in type 2D autosomal recessive limb-girdle muscular dystrophy. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-50170328-C-T is Benign according to our data. Variant chr17-50170328-C-T is described in ClinVar as [Benign]. Clinvar id is 130294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50170328-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.89 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCA	NM_000023.4	c.933C>T	p.Val311=	synonymous_variant	7/10	ENST00000262018.8
SGCA	NM_001135697.3	c.585-312C>T		intron_variant
SGCA	NR_135553.2	n.784-312C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCA	ENST00000262018.8	c.933C>T	p.Val311=	synonymous_variant	7/10	1	NM_000023.4	P1

Frequencies

GnomAD3 genomes AF: 0.0839 AC: 12771 AN: 152128 Hom.: 930 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0461

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.00962

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0417

Gnomad OTH AF: 0.0704

GnomAD3 exomes AF: 0.0422 AC: 10614 AN: 251264 Hom.: 483 AF XY: 0.0384 AC XY: 5215 AN XY: 135800

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.0285

Gnomad ASJ exome AF: 0.0472

Gnomad EAS exome AF: 0.00712

Gnomad SAS exome AF: 0.00964

Gnomad FIN exome AF: 0.0330

Gnomad NFE exome AF: 0.0389

Gnomad OTH exome AF: 0.0398

GnomAD4 exome AF: 0.0430 AC: 62890 AN: 1461472 Hom.: 2020 Cov.: 31 AF XY: 0.0414 AC XY: 30066 AN XY: 726962

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0306

Gnomad4 ASJ exome AF: 0.0465

Gnomad4 EAS exome AF: 0.00796

Gnomad4 SAS exome AF: 0.0107

Gnomad4 FIN exome AF: 0.0331

Gnomad4 NFE exome AF: 0.0424

Gnomad4 OTH exome AF: 0.0480

GnomAD4 genome AF: 0.0840 AC: 12795 AN: 152246 Hom.: 935 Cov.: 32 AF XY: 0.0812 AC XY: 6047 AN XY: 74448

Gnomad4 AFR AF: 0.203

Gnomad4 AMR AF: 0.0461

Gnomad4 ASJ AF: 0.0447

Gnomad4 EAS AF: 0.00944

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0358

Gnomad4 NFE AF: 0.0417

Gnomad4 OTH AF: 0.0697

Alfa AF: 0.0503 Hom.: 391

Bravo AF: 0.0906

Asia WGS AF: 0.0210 AC: 73 AN: 3478

EpiCase AF: 0.0350

EpiControl AF: 0.0377

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Val311Val in exon 7 of SGCA: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 19.8% (874/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1801191). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Feb 08, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 16, 2017

- -

Dystrophin deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Sarcoglycanopathy Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
Cadd	Benign	10
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1801191; hg19: chr17-48247689;