rs2583969

Positions:

• chr4-89824982-T-C

Variant summary

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

The NM_000345.4(SNCA):​c.164-2594A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.188 in 152,058 control chromosomes in the GnomAD database, including 3,380 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 0.19 (3380 hom., cov: 32)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.754

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 (NFE) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNCA	NM_000345.4	c.164-2594A>G		intron_variant		ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.164-2594A>G		intron_variant		1	NM_000345.4	ENSP00000378442	P1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28506 AN: 151940 Hom.: 3378 Cov.: 32

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.351

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.242

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.207

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

GnomAD4 genome AF: 0.188 AC: 28516 AN: 152058 Hom.: 3380 Cov.: 32 AF XY: 0.185 AC XY: 13715 AN XY: 74334

Gnomad4 AFR AF: 0.0651

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.000964

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.242

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.205

Alfa AF: 0.227 Hom.: 544

Bravo AF: 0.180

Asia WGS AF: 0.0620 AC: 217 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.73
DANN	Benign	0.61

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: rs2583969; hg19: chr4-90746133;