rs201106962

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

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. 13/21 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:5

Conservation

PhyloP100: -0.605

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000345.4

BP4

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

BS2

High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCA	NM_000345.4 linkuse as main transcript	c.150T>G	p.His50Gln	missense_variant	3/6	ENST00000394991.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCA	ENST00000394991.8 linkuse as main transcript	c.150T>G	p.His50Gln	missense_variant	3/6	1	NM_000345.4	P1	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

GnomAD3 exomes

AF:

0.0000795

AC:

AN:

251448

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135904

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000238

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152088

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000243

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:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 23, 2023	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) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SNCA: PS3:Supporting -

Autosomal dominant Parkinson disease 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 08, 2014

- -

Lewy body dementia;C1868595:Autosomal dominant Parkinson disease 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2023

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¬†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. -

Parkinson Disease, Dominant

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jul 24, 2016

The SNCA c.150T>G (His50Gln) missense variant has been reported in a heterozygous state in two individuals with Parkinson disease (Appel-Cresswell et al. 2013; Proukakis et al. 2014). Both individuals appeared to share a common haplotype, suggesting a possible founder effect. The p.His50Gln variant was absent from 1325 controls and is reported at a frequency of 0.00003 in the Total population of the Exome Aggregation Consortium. Functional studies demonstrated that the p.His50Gln variant did not significantly alter the structure of the protein but accelerated SNCA fibril aggregation and oligomerization (Ghosh et al. 2013; Khalaf et al. 2014). The variant was also shown to increase SNCA secretion, extracellular toxicity, and cell death (Khalaf et al. 2014; Petrucci et al. 2015). Based on the collective evidence, the p.His50Gln variant is classified as a variant of unknown significance but suspicious for pathogenicity for Parkinson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 06, 2021

- -

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

Dann

Benign

0.42

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;.;.

MutationTaster

Benign

0.96

D;D;D;D;D;D;D;D;D;D

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

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