rs104893937

Positions:

chr5-176621218-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_003085.5(SNCB):c.368C>A(p.Pro123His) variant causes a missense change. The variant allele was found at a frequency of 0.000281 in 1,612,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

SNCB
NM_003085.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1O:1

Conservation

PhyloP100: 4.55

Variant links:

Genes affected

SNCB (HGNC:11140): (synuclein beta) This gene encodes a member of a small family of proteins that inhibit phospholipase D2 and may function in neuronal plasticity. The encoded protein is abundant in lesions of patients with Alzheimer disease. A mutation in this gene was found in individuals with dementia with Lewy bodies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

SNCB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 5-176621218-G-T is Pathogenic according to our data. Variant chr5-176621218-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7026.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, not_provided=1, Uncertain_significance=1}.

BP4

Computational evidence support a benign effect (MetaRNN=0.22367951). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNCB	NM_003085.5 linkuse as main transcript	c.368C>A	p.Pro123His	missense_variant	5/6	ENST00000393693.7	NP_003076.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCB	ENST00000393693.7 linkuse as main transcript	c.368C>A	p.Pro123His	missense_variant	5/6	1	NM_003085.5	ENSP00000377296	P1

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000309

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000169

AC:

AN:

248540

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

134428

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.0000583

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:

0.000311

Gnomad OTH exome

AF:

0.000492

GnomAD4 exome

AF:

0.000289

AC:

422

AN:

1459874

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

214

AN XY:

726130

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000449

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000367

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000204

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000395

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000206

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Lewy body dementia

Pathogenic:2Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Feb 05, 2022	The c.368C>A;p.(Pro123His) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 7026; OMIM: 602569.0002; PMID: 15365127) - PS4_supporting. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 21045828) - PS3. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Synuclein) - PM1. The variant is present at low allele frequencies population databases (rs104893937 – gnomAD 0.002037%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. and allele frequency is greater than expected for disorder - BS1. In summary, the currently available evidence indicates that the variant is likely pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 14, 2004	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant interpreted as Likely pathogenic and reported on 01-14-2020 by Lab PreventionGenetics. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

SNCB-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

The SNCB c.368C>A variant is predicted to result in the amino acid substitution p.Pro123His. This variant was reported in individuals with dementia with Lewy bodies (Ohtake et al. 2004. PubMed ID: 15365127, family study). A functional study showed that transgenic mice expressing this variant developed progressive neurodegeneration (Fujita et al. 2010. Pubmed ID: 21045828). Other studies elaborated on the mechanism of this variant (Janowska et al 2015. PubMed ID: 26332674; Psol et al. 2021. PubMed ID: 33760043). However, family segregation study shows that this variant does not produce a disease phenotype in all individuals suggesting reduced penetrance for this variant (Ohtake et al. 2004. PubMed ID: 15365127). This variant is reported in 0.036% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

AiLife Diagnostics, AiLife Diagnostics

Mar 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Uncertain

0.050

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.57

D;T;D;D;D

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

.;D;.;.;T

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Uncertain

0.35

MutationAssessor

Benign

1.9

L;.;L;L;L

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.68

N;.;N;N;N

REVEL

Uncertain

0.59

Sift

Uncertain

0.0090

D;.;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D

Polyphen

0.98

D;.;D;D;D

Vest4

0.40

MVP

0.97

MPC

0.60

ClinPred

0.051

GERP RS

5.2

Varity_R

0.20

gMVP

0.46

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