rs775468466

Positions:

• chr7-94600827-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003919.3(SGCE):​c.856C>G​(p.Gln286Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,459,890 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: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SGCE NM_003919.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.92

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29663482).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCE	NM_003919.3	c.856C>G	p.Gln286Glu	missense_variant	7/11	ENST00000648936.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCE	ENST00000648936.2	c.856C>G	p.Gln286Glu	missense_variant	7/11		NM_003919.3	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249188 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134668

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000110 AC: 16 AN: 1459890 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726154

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myoclonic dystonia 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Feb 13, 2018	In summary, the available evidence is currently insufficient to determine the role of this variant 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 SGCE-related disease. This variant is present in population databases (rs775468466, ExAC 0.002%). This sequence change replaces glutamine with glutamic acid at codon 286 of the SGCE protein (p.Gln286Glu). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	23
DANN	Benign	0.39
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.087
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D;.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.30	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;T;T;T
MetaSVM	Uncertain	0.31	D
MutationTaster	Benign	0.97	D;D;D;D;D;D
PrimateAI	Benign	0.46	T
Polyphen		0.037, 0.18, 0.069, 0.47	.;B;B;.;B;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.
Vest4		0.25, 0.24, 0.28, 0.27, 0.28
MutPred		0.43		.;.;.;.;.;Loss of sheet (P = 0.1158);.;.;.;.;.;.;.;.;.;Loss of sheet (P = 0.1158);.;.;.;.;Loss of sheet (P = 0.1158);.;.;.;.;.;.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;.;Loss of sheet (P = 0.1158);Loss of sheet (P = 0.1158);.;.;
MVP		0.84
MPC		0.21
ClinPred		0.21	T
GERP RS		3.9
Varity_R		0.10
gMVP		0.27

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: rs775468466; hg19: chr7-94230139;