rs2619369

Variant names:

• chr4-89812518-A-G
• rs2619369
• NM_000345.4:c.306+9728T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000345.4(SNCA):​c.306+9728T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 152,290 control chromosomes in the GnomAD database, including 49 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 0.021 (49 hom., cov: 32)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.324
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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: 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=-0.84).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0208 (3166/152290) while in subpopulation NFE AF = 0.0285 (1938/68018). AF 95% confidence interval is 0.0274. There are 49 homozygotes in GnomAd4. There are 1621 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 49 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000345.4. 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
	SNCA	NM_000345.4	MANE Select	c.306+9728T>C		intron	N/A	NP_000336.1	P37840-1
	SNCA	NM_001146054.2		c.306+9728T>C		intron	N/A	NP_001139526.1	P37840-1
	SNCA	NM_001146055.2		c.306+9728T>C		intron	N/A	NP_001139527.1	P37840-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNCA	ENST00000394991.8	TSL:1 MANE Select	c.306+9728T>C		intron	N/A	ENSP00000378442.4	P37840-1
	SNCA	ENST00000394986.5	TSL:1	c.306+9728T>C		intron	N/A	ENSP00000378437.1	P37840-1
	SNCA	ENST00000394989.6	TSL:1	c.264+9728T>C		intron	N/A	ENSP00000378440.2	P37840-3

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3165 AN: 152172 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.00425

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0228

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.0507

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0187

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

GnomAD4 genome AF: 0.0208 AC: 3166 AN: 152290 Hom.: 49 Cov.: 32 AF XY: 0.0218 AC XY: 1621 AN XY: 74490

African (AFR) AF: 0.00423 AC: 176 AN: 41576

American (AMR) AF: 0.0124 AC: 189 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0228 AC: 79 AN: 3466

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.0213 AC: 103 AN: 4830

European-Finnish (FIN) AF: 0.0507 AC: 538 AN: 10612

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0285 AC: 1938 AN: 68018

Other (OTH) AF: 0.0185 AC: 39 AN: 2110

Alfa AF: 0.0244 Hom.: 82

Bravo AF: 0.0169

Asia WGS AF: 0.00837 AC: 29 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.3
DANN	Benign	0.89
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

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: rs2619369; hg19: chr4-90733669;