rs201106962

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1BP4_Moderate

The NM_000345.4(SNCA):c.150T>G(p.His50Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000182 in 1,613,152 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

SNCA
NM_000345.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:6

Conservation

PhyloP100: -0.605

Publications

576 publications found

Variant links:

Genes affected

SNCA (HGNC:11138): (synuclein alpha) Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer's disease. Alternatively spliced transcripts encoding different isoforms have been identified for this gene. [provided by RefSeq, Feb 2016]

SNCA Gene-Disease associations (from GenCC):

autosomal dominant Parkinson disease 4
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Parkinson disease
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
autosomal dominant Parkinson disease 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
Lewy body dementia
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
hereditary late onset Parkinson disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
parkinsonian-pyramidal syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SNCA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 0 uncertain in NM_000345.4

BP4

Computational evidence support a benign effect (MetaRNN=0.12971321).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4 link	c.150T>G	p.His50Gln	missense_variant	Exon 3 of 6	ENST00000394991.8	NP_000336.1	P37840-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8 link	c.150T>G	p.His50Gln	missense_variant	Exon 3 of 6	1	NM_000345.4	ENSP00000378442.4		P37840-1

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000162

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000795

AC:

AN:

251448

AF XY:

0.0000441

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000192

AC:

280

AN:

1461064

Hom.:

Cov.:

AF XY:

0.000186

AC XY:

135

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86236

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000238

AC:

264

AN:

1111400

Other (OTH)

AF:

0.000232

AC:

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0000855

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000163

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Sep 27, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS2, PS3, PS4_moderate -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SNCA: PS3:Supporting -

Mar 23, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect leading to accelerated protein aggregation (Ghosh et al., 2013; Porcari et al., 2015; Rutherford et al., 2014); Reported in patients with dopa-responsive Parkinson disease in published literature (Appel-Cresswell et al., 2013; Proukakis et al., 2013); Reported as a somatic variant in brain tissue of an individual with sporadic late-onset Parkinson disease (Proukakis et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26306801, 31980526, 29398121, 23669636, 26076669, 25330418, 26341711, 25554495, 24728187, 25505181, 24984882, 24936070, 25393002, 27573854, 30528390, 31996268, 23916651, 27250986, 23674458, 28650719, 24047453, 23674490, 23427326, 24315198, 23457019, 36099961) -

Lewy body dementia;C1854182:Autosomal dominant Parkinson disease 4;C1868595:Autosomal dominant Parkinson disease 1

Uncertain:2

Dec 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 30, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Autosomal dominant Parkinson disease 1

Pathogenic:1

Aug 08, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Lewy body dementia;C1868595:Autosomal dominant Parkinson disease 1

Uncertain:1

Nov 25, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 50 of the SNCA protein (p.His50Gln). This variant is present in population databases (rs201106962, gnomAD 0.01%). This missense change has been observed in individual(s) with Parkinson's disease (PMID: 23427326, 23457019, 29398121). ClinVar contains an entry for this variant (Variation ID: 162095). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†is likely to be tolerated. Experimental studies have shown that this missense change affects SNCA function (PMID: 23427326, 30528390). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.38

.;T;.;T;T;T;T;.;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.78

T;.;.;.;.;.;T;T;T

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.13

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-0.11

N;N;N;N;N;N;N;.;.

PhyloP100

-0.60

PrimateAI

Uncertain

0.71

PROVEAN

Benign

0.86

N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

1.0

T;T;T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T;T;.

Polyphen

0.0

B;B;B;B;B;B;B;.;.

Vest4

0.49

MutPred

0.38

Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);

MVP

0.98

MPC

0.35

ClinPred

0.0038

GERP RS

-2.2

Varity_R

0.17

gMVP

0.72

Mutation Taster

=0/100

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over