rs104893937

chr5-176621218-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5 BP4 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 O:1
• Conservation: PhyloP100: 4.55

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]

ACMG classification

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: {Pathogenic=1, Uncertain_significance=1, Likely_pathogenic=1, not_provided=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22367951).. Strength limited to SUPPORTING due to the PP5.
• BS2: High AC in GnomAd at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCB	NM_003085.5	c.368C>A	p.Pro123His	missense_variant	5/6	ENST00000393693.7

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152154 Hom.: 0 Cov.: 32

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: 42 AN: 248540 Hom.: 0 AF XY: 0.000164 AC XY: 22 AN XY: 134428

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.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 214 AN XY: 726130

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: 31 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74452

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.: 0

Bravo AF: 0.000170

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000206 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000595

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Lewy body dementia Pathogenic:2 Other: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 condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 30, 2023

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 (http://gnomad.broadinstitute.org/variant/5-176048219-G-T). 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	T
BayesDel_noAF	Uncertain	0.050
Cadd	Benign	21
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	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	1.9	L;.;L;L;L
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Benign	0.44	T
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	T
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

Other links and lift over

dbSNP: rs104893937; hg19: chr5-176048219; COSMIC: COSV100031159;