rs533652380

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001346713.2(SGCE):​c.1144G>A​(p.Val382Met) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V382V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SGCE NM_001346713.2 missense, splice_region
• Scores: Splicing: ADA: 0.003243
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.77
• Publications: 4 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=0.29139462).
• BS2: High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001346713.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCE	NM_003919.3	MANE Select	c.1036G>A	p.Val346Met	missense splice_region	Exon 7 of 11	NP_003910.1
	SGCE	NM_001346713.2		c.1144G>A	p.Val382Met	missense splice_region	Exon 8 of 12	NP_001333642.1
	SGCE	NM_001346715.2		c.1144G>A	p.Val382Ile	missense splice_region	Exon 8 of 11	NP_001333644.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCE	ENST00000648936.2	MANE Select	c.1036G>A	p.Val346Met	missense splice_region	Exon 7 of 11	ENSP00000497130.1
	SGCE	ENST00000428696.7	TSL:1	c.1015G>A	p.Val339Ile	missense splice_region	Exon 7 of 11	ENSP00000397536.3
	SGCE	ENST00000447873.6	TSL:1	c.1036G>A	p.Val346Ile	missense splice_region	Exon 7 of 10	ENSP00000388734.1

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

GnomAD2 exomes AF: 0.0000441 AC: 11 AN: 249314 AF XY: 0.0000445

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 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

African (AFR) AF: 0.0000300 AC: 1 AN: 33388

American (AMR) AF: 0.0000224 AC: 1 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.000767 AC: 20 AN: 26078

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39628

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1108178

Other (OTH) AF: 0.0000664 AC: 4 AN: 60224

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41554

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000577 AC: 2 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2110

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Myoclonic dystonia 11 (2)
-	2	-	not provided (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.29	T
MetaSVM	Pathogenic	0.94	D
PhyloP100		5.8
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
PromoterAI		0.018	Neutral
Varity_R		0.14
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs533652380; hg19: chr7-94229959; COSMIC: COSV56015681; COSMIC: COSV56015681;