rs370609227

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BS1_SupportingBS2

The NM_003919.3(SGCE):c.391A>G(p.Ile131Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,590,418 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/24 in silico tools predict 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I131T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 1 hom. )

Consequence

SGCE
NM_003919.3 missense, splice_region

Scores

Splicing: ADA: 0.0009372

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 7.48

Publications

2 publications found

Variant links:

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]

SGCE links:

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]

CASD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.30583572).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000138 (21/152178) while in subpopulation NFE AF = 0.000294 (20/68028). AF 95% confidence interval is 0.000194. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 21 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003919.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGCE	NM_003919.3	MANE Select	c.391A>G	p.Ile131Val	missense splice_region	Exon 4 of 11	NP_003910.1	A0A0S2Z4P5
SGCE	NM_001346713.2		c.499A>G	p.Ile167Val	missense splice_region	Exon 5 of 12	NP_001333642.1	A0A2R8YGQ3
SGCE	NM_001346715.2		c.499A>G	p.Ile167Val	missense splice_region	Exon 5 of 11	NP_001333644.1	A0A2R8Y5J3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SGCE	ENST00000648936.2	MANE Select	c.391A>G	p.Ile131Val	missense splice_region	Exon 4 of 11	ENSP00000497130.1	O43556-1
SGCE	ENST00000428696.7	TSL:1	c.391A>G	p.Ile131Val	missense splice_region	Exon 4 of 11	ENSP00000397536.3	A0A2U3TZN7
SGCE	ENST00000447873.6	TSL:1	c.391A>G	p.Ile131Val	missense splice_region	Exon 4 of 10	ENSP00000388734.1	C9JR67

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000182

AC:

AN:

247766

AF XY:

0.000172

show subpopulations

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:

0.000139

Gnomad NFE exome

AF:

0.000366

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000181

AC:

261

AN:

1438240

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

123

AN XY:

716710

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32858

American (AMR)

AF:

0.0000225

AC:

AN:

44472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25932

East Asian (EAS)

AF:

0.00

AC:

AN:

39386

South Asian (SAS)

AF:

0.00

AC:

AN:

85058

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.000232

AC:

253

AN:

1092068

Other (OTH)

AF:

0.000101

AC:

AN:

59522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000138

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000336

Hom.:

Bravo

AF:

0.000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000234

AC:

ExAC

AF:

0.000255

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Myoclonic dystonia 11 (3)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.013

BayesDel_noAF

Uncertain

0.060

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.31

Eigen

Benign

0.094

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.038

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

0.74

PhyloP100

7.5

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.21

REVEL

Uncertain

0.54

Sift

Benign

0.43

Sift4G

Benign

0.44

Polyphen

0.28

Vest4

0.60

MVP

0.79

MPC

0.34

ClinPred

0.18

GERP RS

5.3

Varity_R

0.093

gMVP

0.39

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00094

dbscSNV1_RF

Benign

0.026

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over