rs2737020

Variant names:

• chr4-89819727-G-A
• rs2737020
• NM_000345.4:c.306+2519C>T

Variant summary

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

The NM_000345.4(SNCA):​c.306+2519C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.674 in 151,946 control chromosomes in the GnomAD database, including 35,054 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 0.67 (35054 hom., cov: 31)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.507
• Publications: 9 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.306+2519C>T		intron_variant	Intron 4 of 5	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.306+2519C>T		intron_variant	Intron 4 of 5	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.675 AC: 102418 AN: 151828 Hom.: 35031 Cov.: 31

Gnomad AFR AF: 0.622

Gnomad AMI AF: 0.795

Gnomad AMR AF: 0.598

Gnomad ASJ AF: 0.602

Gnomad EAS AF: 0.661

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.742

Gnomad MID AF: 0.595

Gnomad NFE AF: 0.730

Gnomad OTH AF: 0.660

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

GnomAD4 genome AF: 0.674 AC: 102485 AN: 151946 Hom.: 35054 Cov.: 31 AF XY: 0.670 AC XY: 49744 AN XY: 74266

African (AFR) AF: 0.622 AC: 25780 AN: 41444

American (AMR) AF: 0.597 AC: 9102 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.602 AC: 2086 AN: 3466

East Asian (EAS) AF: 0.661 AC: 3395 AN: 5138

South Asian (SAS) AF: 0.502 AC: 2422 AN: 4822

European-Finnish (FIN) AF: 0.742 AC: 7827 AN: 10552

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.730 AC: 49585 AN: 67960

Other (OTH) AF: 0.657 AC: 1385 AN: 2108

Alfa AF: 0.689 Hom.: 4750

Bravo AF: 0.668

Asia WGS AF: 0.570 AC: 1984 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.4
DANN	Benign	0.55
PhyloP100		0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2737020; hg19: chr4-90740878;