rs356219

Variant names:

• chr4-89716450-G-A
• rs356219
• ENST00000673902.1:c.390+12744C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000673902.1(SNCA):​c.390+12744C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 151,896 control chromosomes in the GnomAD database, including 23,595 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.54 (23595 hom., cov: 31)
• Consequence: SNCA ENST00000673902.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 186 publications found

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: Ambry Genetics, ClinGen
• autosomal dominant Parkinson disease 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Lewy body dementia

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parkinsonian-pyramidal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000251095 (HGNC:53614):

LOC124900602 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.633 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000673902.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	ENST00000673902.1		c.390+12744C>T		intron	N/A	ENSP00000501102.1	A0A669KB41
	ENSG00000251095	ENST00000507916.6	TSL:3	n.256-3376G>A		intron	N/A
	ENSG00000251095	ENST00000508021.5	TSL:4	n.448-9934G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.544 AC: 82608 AN: 151778 Hom.: 23588 Cov.: 31

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.609

Gnomad AMR AF: 0.555

Gnomad ASJ AF: 0.618

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.585

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.638

Gnomad OTH AF: 0.539

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.544 AC: 82647 AN: 151896 Hom.: 23595 Cov.: 31 AF XY: 0.545 AC XY: 40439 AN XY: 74262

African (AFR) AF: 0.359 AC: 14862 AN: 41408

American (AMR) AF: 0.555 AC: 8473 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.618 AC: 2147 AN: 3472

East Asian (EAS) AF: 0.468 AC: 2413 AN: 5160

South Asian (SAS) AF: 0.585 AC: 2817 AN: 4814

European-Finnish (FIN) AF: 0.638 AC: 6717 AN: 10522

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.638 AC: 43345 AN: 67944

Other (OTH) AF: 0.538 AC: 1137 AN: 2112

Alfa AF: 0.583 Hom.: 28329

Bravo AF: 0.525

Asia WGS AF: 0.495 AC: 1722 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.0
DANN	Benign	0.19
PhyloP100		-0.062

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs356219;

hg19: chr4-90637601;