dbSNP rs1064794321: SGCE:p.Leu184Pro (chr7-94618869-A-G) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001346713.2(SGCE):c.659T>C(p.Leu220Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L220F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SGCE
NM_001346713.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:1

Conservation

PhyloP100: 9.32

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

PP5

Variant 7-94618869-A-G is Pathogenic according to our data. Variant chr7-94618869-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 420156.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SGCE	NM_003919.3	MANE Select	c.551T>C	p.Leu184Pro	missense	Exon 5 of 11	NP_003910.1
SGCE	NM_001346713.2		c.659T>C	p.Leu220Pro	missense	Exon 6 of 12	NP_001333642.1
SGCE	NM_001346715.2		c.659T>C	p.Leu220Pro	missense	Exon 6 of 11	NP_001333644.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SGCE	ENST00000648936.2	MANE Select	c.551T>C	p.Leu184Pro	missense	Exon 5 of 11	ENSP00000497130.1
SGCE	ENST00000428696.7	TSL:1	c.530T>C	p.Leu177Pro	missense	Exon 5 of 11	ENSP00000397536.3
SGCE	ENST00000447873.6	TSL:1	c.551T>C	p.Leu184Pro	missense	Exon 5 of 10	ENSP00000388734.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Myoclonic dystonia 11 (2)

not provided (2)

Myoclonus-dystonia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.93

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.3

PhyloP100

9.3

PrimateAI

Pathogenic

0.95

PROVEAN

Uncertain

-2.7

REVEL

Pathogenic

0.90

Sift

Benign

0.044

Sift4G

Benign

0.095

Polyphen

1.0

Vest4

0.95

MutPred

0.81

Loss of stability (P = 0.0322)

MVP

0.92

MPC

0.98

ClinPred

0.96

GERP RS

5.7

Varity_R

0.81

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over