rs183951730

Positions:

• chr7-94597961-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003919.3(SGCE):​c.1253+814G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 163,474 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0084 (1 hom.)
• Consequence: SGCE NM_003919.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.504

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01735276).
• BP6: Variant 7-94597961-C-T is Benign according to our data. Variant chr7-94597961-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94597961-C-T is described in Lovd as [Benign]. Variant chr7-94597961-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00869 (1315/151318) while in subpopulation NFE AF= 0.0127 (864/67856). AF 95% confidence interval is 0.012. There are 8 homozygotes in gnomad4. There are 609 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1315 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCE	NM_003919.3	c.1253+814G>A		intron_variant		ENST00000648936.2	NP_003910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCE	ENST00000648936.2	c.1253+814G>A		intron_variant			NM_003919.3	ENSP00000497130	A1

Frequencies

GnomAD3 genomes AF: 0.00870 AC: 1315 AN: 151208 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.00399

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.00870

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.00567

Gnomad FIN AF: 0.00289

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.0127

Gnomad OTH AF: 0.0130

GnomAD3 exomes AF: 0.00609 AC: 19 AN: 3120 Hom.: 0 AF XY: 0.00894 AC XY: 17 AN XY: 1902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00718

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00347

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00730

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00839 AC: 102 AN: 12156 Hom.: 1 Cov.: 0 AF XY: 0.00861 AC XY: 73 AN XY: 8480

Gnomad4 AFR exome AF: 0.0174

Gnomad4 AMR exome AF: 0.00664

Gnomad4 ASJ exome AF: 0.0211

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00433

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00926

Gnomad4 OTH exome AF: 0.0100

GnomAD4 genome AF: 0.00869 AC: 1315 AN: 151318 Hom.: 8 Cov.: 31 AF XY: 0.00824 AC XY: 609 AN XY: 73896

Gnomad4 AFR AF: 0.00398

Gnomad4 AMR AF: 0.00869

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.00214

Gnomad4 SAS AF: 0.00567

Gnomad4 FIN AF: 0.00289

Gnomad4 NFE AF: 0.0127

Gnomad4 OTH AF: 0.0129

Alfa AF: 0.00974 Hom.: 2

Bravo AF: 0.00900

TwinsUK AF: 0.0138 AC: 51

ALSPAC AF: 0.0161 AC: 62

ExAC AF: 0.00458 AC: 48

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SGCE: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Myoclonic dystonia 11 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.8
DANN	Uncertain	1.0
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.0034	N
LIST_S2	Benign	0.63	T;T;T;T;T
MetaRNN	Benign	0.017	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PROVEAN	Benign	-0.040	N;.;.;.;.
REVEL	Benign	0.029
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Benign	0.51	T;.;.;.;.
Vest4		0.065
MVP		0.32
MPC		0.19
ClinPred		0.068	T
GERP RS		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs183951730; hg19: chr7-94227273;