rs755191122

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003919.3(SGCE):c.5A>C(p.Gln2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000937 in 1,600,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000083 ( 0 hom. )

Consequence

SGCE
NM_003919.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0260

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.22191033).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SGCE	NM_003919.3 linkuse as main transcript	c.5A>C	p.Gln2Pro	missense_variant	1/11	ENST00000648936.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SGCE	ENST00000648936.2 linkuse as main transcript	c.5A>C	p.Gln2Pro	missense_variant	1/11		NM_003919.3	A1	O43556-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152094

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249918

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135404

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000886

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000828

AC:

AN:

1448898

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

721814

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000109

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Myoclonic dystonia 11

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 05, 2023

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The proline amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 566714). This variant has not been reported in the literature in individuals affected with SGCE-related conditions. This variant is present in population databases (rs755191122, gnomAD 0.003%). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 2 of the SGCE protein (p.Gln2Pro). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.12

Cadd

Benign

Dann

Benign

0.79

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.078

LIST_S2

Uncertain

0.89

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

0.15

MetaRNN

Benign

0.22

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

0.42

MutationTaster

Benign

0.99

N;N;N;N;N;N

PrimateAI

Uncertain

0.69

Polyphen

0.46, 0.0

.;.;P;.;P;.;.;.;P;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;B;.;.;.

Vest4

0.38, 0.35, 0.47, 0.43, 0.41, 0.40

MutPred

0.34

Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);Gain of catalytic residue at Q2 (P = 0.0022);

MVP

0.78

MPC

0.42

ClinPred

0.040

GERP RS

-1.3

Varity_R

0.14

gMVP

0.25

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over