rs762287154

Positions:

• chr7-94600778-T-A

Variant summary

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

The NM_003919.3(SGCE):​c.905A>T​(p.Lys302Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000297 in 1,613,516 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K302N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: SGCE NM_003919.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 3.88

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=0.38649654).
• BS2: High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCE	NM_003919.3	c.905A>T	p.Lys302Ile	missense_variant	7/11	ENST00000648936.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCE	ENST00000648936.2	c.905A>T	p.Lys302Ile	missense_variant	7/11		NM_003919.3	A1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250442 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135338

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461370 Hom.: 1 Cov.: 31 AF XY: 0.0000248 AC XY: 18 AN XY: 726992

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74318

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000106

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myoclonic dystonia 11 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	This sequence change replaces lysine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 302 of the SGCE protein (p.Lys302Ile). This variant is present in population databases (rs762287154, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of dystonia and related disorders (Invitae). ClinVar contains an entry for this variant (Variation ID: 532784). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SGCE protein function with a negative predictive value of 80%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 03, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.905A>T (p.K302I) alteration is located in exon 7 (coding exon 7) of the SGCE gene. This alteration results from a A to T substitution at nucleotide position 905, causing the lysine (K) at amino acid position 302 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.049	T
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	23
DANN	Uncertain	0.99
Eigen	Benign	0.022
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	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	Uncertain	0.20	D
MetaRNN	Benign	0.39	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	0.71	D
MutationTaster	Benign	0.83	D;D;D;D;D;D
PrimateAI	Uncertain	0.54	T
Polyphen		0.60, 0.79, 0.37, 0.83	.;P;P;.;P;.;.;.;B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.
Vest4		0.45, 0.44, 0.45, 0.47, 0.45
MutPred		0.50		.;.;.;.;.;Loss of ubiquitination at K338 (P = 0.0023);.;.;.;.;.;.;.;.;.;Loss of ubiquitination at K338 (P = 0.0023);.;.;.;.;Loss of ubiquitination at K338 (P = 0.0023);.;.;.;.;.;.;Loss of ubiquitination at K338 (P = 0.0023);Loss of ubiquitination at K338 (P = 0.0023);.;.;.;Loss of ubiquitination at K338 (P = 0.0023);Loss of ubiquitination at K338 (P = 0.0023);.;.;
MVP		0.87
MPC		0.51
ClinPred		0.19	T
GERP RS		4.5
Varity_R		0.099
gMVP		0.51

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: rs762287154; hg19: chr7-94230090;