rs533652380

Variant names:

• chr7-94600647-C-T
• rs533652380
• NM_003919.3:c.1036G>A

Variant summary

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

The NM_003919.3(SGCE):​c.1036G>A​(p.Val346Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000975 in 1,609,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SGCE NM_003919.3 missense, splice_region
• Scores: Splicing: ADA: 0.003243
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 5.77

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

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.29139462).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGCE	NM_003919.3	c.1036G>A	p.Val346Met	missense_variant, splice_region_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.1036G>A	p.Val346Met	missense_variant, splice_region_variant	Exon 7 of 11		NM_003919.3	ENSP00000497130.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000441 AC: 11 AN: 249314 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134792

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000656

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 152 AN: 1457312 Hom.: 0 Cov.: 29 AF XY: 0.000103 AC XY: 75 AN XY: 725324

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000767

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.0000664

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74412

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000567

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myoclonic dystonia 11 Uncertain:2

Dec 18, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 346 of the SGCE protein (p.Val346Met). This variant is present in population databases (rs533652380, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with SGCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 464149). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Inborn genetic diseases Uncertain:1

Feb 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1036G>A (p.V346M) alteration is located in exon 7 (coding exon 7) of the SGCE gene. This alteration results from a G to A substitution at nucleotide position 1036, causing the valine (V) at amino acid position 346 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	31
DANN	Benign	0.93
DEOGEN2	Benign	0.38	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T;T;T;.;T;T;T;T;T;T;T;T;T;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.94	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.27	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.41
Sift	Benign	0.52	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Benign	0.25	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Polyphen		0.024	B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.30
MVP		0.82
ClinPred		0.37	T
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0032
dbscSNV1_RF	Benign	0.048
SpliceAI score (max)		0.010		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: rs533652380; hg19: chr7-94229959; COSMIC: COSV56015681; COSMIC: COSV56015681;