NM_003919.3:c.856C>G

Variant names:

• chr7-94600827-G-C
• rs775468466
• NM_003919.3:c.856C>G

Variant summary

Our verdict is Likely benign. The variant received -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
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
SGCE	NM_003919.3	c.856C>G	p.Gln286Glu	missense_variant	Exon 7 of 11	ENST00000648936.2	NP_003910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGCE	ENST00000648936.2	c.856C>G	p.Gln286Glu	missense_variant	Exon 7 of 11		NM_003919.3	ENSP00000497130.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000803 AC: 2 AN: 249188 AF XY: 0.00000743

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86008

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53324

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5200

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111336

Other (OTH) AF: 0.0000166 AC: 1 AN: 60272

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

Feb 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 13, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
DEOGEN2	Benign	0.27	.;T;D;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.
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
MutationAssessor	Benign	0.30	.;.;N;.;N;.;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		6.9
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.31	.;N;.;.;N;.;.;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.
REVEL	Uncertain	0.56
Sift	Benign	1.0	.;T;.;.;T;.;.;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.
Sift4G	Benign	1.0	.;T;.;.;T;.;.;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;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
PromoterAI		0.0074	Neutral
Varity_R		0.10
gMVP		0.27
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs775468466; hg19: chr7-94230139;