4-89704960-G-A

Variant names:

• chr4-89704960-G-A
• rs356182
• ENST00000673902.1:c.391-2576C>T

Variant summary

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

The ENST00000673902.1(SNCA):​c.391-2576C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.648 in 151,816 control chromosomes in the GnomAD database, including 32,205 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 0.65 (32205 hom., cov: 33)
• Consequence: SNCA ENST00000673902.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.846
• Publications: 91 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: 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

ENSG00000251095 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.677 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LOC124900602	XR_007058466.1	n.9901+13555G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000673902.1	c.391-2576C>T		intron_variant	Intron 5 of 6			ENSP00000501102.1
ENSG00000251095	ENST00000507916.6	n.255+13555G>A		intron_variant	Intron 2 of 2	3
ENSG00000251095	ENST00000508021.5	n.447+13555G>A		intron_variant	Intron 4 of 4	4

Frequencies

GnomAD3 genomes AF: 0.648 AC: 98318 AN: 151698 Hom.: 32183 Cov.: 33

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.659

Gnomad AMR AF: 0.606

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.338

Gnomad SAS AF: 0.640

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.742

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.628

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

GnomAD4 genome AF: 0.648 AC: 98392 AN: 151816 Hom.: 32205 Cov.: 33 AF XY: 0.645 AC XY: 47822 AN XY: 74150

African (AFR) AF: 0.684 AC: 28345 AN: 41456

American (AMR) AF: 0.606 AC: 9240 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2355 AN: 3462

East Asian (EAS) AF: 0.339 AC: 1744 AN: 5152

South Asian (SAS) AF: 0.639 AC: 3082 AN: 4820

European-Finnish (FIN) AF: 0.649 AC: 6828 AN: 10522

Middle Eastern (MID) AF: 0.736 AC: 215 AN: 292

European-Non Finnish (NFE) AF: 0.658 AC: 44665 AN: 67834

Other (OTH) AF: 0.625 AC: 1318 AN: 2108

Alfa AF: 0.640 Hom.: 47131

Bravo AF: 0.639

Asia WGS AF: 0.511 AC: 1778 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.4
DANN	Benign	0.77
PhyloP100		0.85

Splicing

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

Other links and lift over

dbSNP: rs356182; hg19: chr4-90626111;