rs17166384

Positions:

• chr7-94623400-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_003919.3(SGCE):​c.391-3T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,582,944 control chromosomes in the GnomAD database, including 2,719 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.076 (1498 hom., cov: 32)
  • Exomes 𝑓: 0.0078 (1221 hom.)
• Consequence: SGCE NM_003919.3 splice_region, intron
• Scores: Splicing: ADA: 0.0004597
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.03

Genes affected

SGCE (HGNC:10808): (sarcoglycan epsilon) This gene encodes the epsilon member of the sarcoglycan family. Sarcoglycans are transmembrane proteins that are components of the dystrophin-glycoprotein complex, which link the actin cytoskeleton to the extracellular matrix. Unlike other family members which are predominantly expressed in striated muscle, the epsilon sarcoglycan is more broadly expressed. Mutations in this gene are associated with myoclonus-dystonia syndrome. This gene is imprinted, with preferential expression from the paternal allele. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. A pseudogene associated with this gene is located on chromosome 2. [provided by RefSeq, Oct 2016]

CASD1 (HGNC:16014): (CAS1 domain containing 1) Enables N-acetylneuraminate 7-O(or 9-O)-acetyltransferase activity. Involved in carbohydrate metabolic process. Is integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

SGCE (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 7-94623400-A-G is Benign according to our data. Variant chr7-94623400-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 197225.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94623400-A-G is described in Lovd as [Benign]. Variant chr7-94623400-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.259 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCE	NM_003919.3	c.391-3T>C		splice_region_variant, intron_variant		ENST00000648936.2	NP_003910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCE	ENST00000648936.2	c.391-3T>C		splice_region_variant, intron_variant			NM_003919.3	ENSP00000497130.1

Frequencies

GnomAD3 genomes AF: 0.0758 AC: 11531 AN: 152078 Hom.: 1495 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0284

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.0516

GnomAD3 exomes AF: 0.0200 AC: 4940 AN: 246722 Hom.: 591 AF XY: 0.0146 AC XY: 1947 AN XY: 133510

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.0139

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000404

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00118

Gnomad OTH exome AF: 0.00849

GnomAD4 exome AF: 0.00781 AC: 11178 AN: 1430748 Hom.: 1221 Cov.: 24 AF XY: 0.00675 AC XY: 4814 AN XY: 713342

Gnomad4 AFR exome AF: 0.265

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.00139

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000401

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000747

Gnomad4 OTH exome AF: 0.0159

GnomAD4 genome AF: 0.0759 AC: 11557 AN: 152196 Hom.: 1498 Cov.: 32 AF XY: 0.0730 AC XY: 5430 AN XY: 74410

Gnomad4 AFR AF: 0.263

Gnomad4 AMR AF: 0.0283

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.0515

Alfa AF: 0.0261 Hom.: 352

Bravo AF: 0.0856

Asia WGS AF: 0.0120 AC: 41 AN: 3454

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	This variant is associated with the following publications: (PMID: 30849405, 27884173, 15728306) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jan 18, 2019	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2014	- -

Myoclonic dystonia 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	12
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00046
dbscSNV1_RF	Benign	0.010
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

Other links and lift over

dbSNP: rs17166384; hg19: chr7-94252712;