rs1866995

Positions:

• chr4-89810558-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000345.4(SNCA):​c.306+11688T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0727 in 152,230 control chromosomes in the GnomAD database, including 714 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 0.073 (714 hom., cov: 32)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.437

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SNCA	NM_000345.4	c.306+11688T>C		intron_variant		ENST00000394991.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SNCA	ENST00000394991.8	c.306+11688T>C		intron_variant		1	NM_000345.4	P1

Frequencies

GnomAD3 genomes AF: 0.0727 AC: 11052 AN: 152112 Hom.: 712 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.0548

Gnomad AMR AF: 0.0356

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0218

Gnomad FIN AF: 0.0269

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0414

Gnomad OTH AF: 0.0551

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

GnomAD4 genome AF: 0.0727 AC: 11070 AN: 152230 Hom.: 714 Cov.: 32 AF XY: 0.0697 AC XY: 5191 AN XY: 74426

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.0355

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0218

Gnomad4 FIN AF: 0.0269

Gnomad4 NFE AF: 0.0414

Gnomad4 OTH AF: 0.0545

Alfa AF: 0.0429 Hom.: 295

Bravo AF: 0.0786

Asia WGS AF: 0.0270 AC: 92 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.2
DANN	Benign	0.42

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: rs1866995; hg19: chr4-90731709;