rs773531358

chr7-94656022-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003919.3(SGCE):c.77G>A(p.Ser26Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SGCE NM_003919.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23846492).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCE	NM_003919.3	c.77G>A	p.Ser26Asn	missense_variant	1/11	ENST00000648936.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCE	ENST00000648936.2	c.77G>A	p.Ser26Asn	missense_variant	1/11		NM_003919.3	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249778 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135364

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460290 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726586

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Myoclonic dystonia 11 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 30, 2019

In summary, this variant has uncertain impact on SGCE function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with a SGCE-related disease. This variant is present in population databases (rs773531358, ExAC 0.006%). This sequence change replaces serine with asparagine at codon 26 of the SGCE protein (p.Ser26Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.83	T;T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	0.54	D;D;D;D;N;N
PrimateAI	Pathogenic	0.80	T
Polyphen		0.14, 0.27, 0.53	.;.;B;.;B;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.
Vest4		0.58, 0.56, 0.55, 0.51, 0.58, 0.50
MutPred		0.15		Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);Loss of phosphorylation at S26 (P = 0.0241);
MVP		0.78
MPC		0.26
ClinPred		0.41	T
GERP RS		3.1
Varity_R		0.22
gMVP		0.59

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: rs773531358; hg19: chr7-94285334;