rs2301134

Positions:

• chr4-89837794-A-G
• chr4-89837794-A-T

Variant summary

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

The NM_001146055.2(SNCA):​c.-26+458T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 151,940 control chromosomes in the GnomAD database, including 25,384 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 0.57 (25384 hom., cov: 31)
• Consequence: SNCA NM_001146055.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0680

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-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNCA	NM_001146055.2	c.-26+458T>C		intron_variant			NP_001139527.1
SNCA	NM_001375285.1	c.-95+458T>C		intron_variant			NP_001362214.1
SNCA	XM_011532205.3	c.-26+458T>C		intron_variant			XP_011530507.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000336904.7	c.-26+458T>C		intron_variant		2		ENSP00000338345.3
SNCA-AS1	ENST00000501215.1	n.312-467A>G		intron_variant		2
SNCA-AS1	ENST00000513653.1	n.328-467A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86626 AN: 151822 Hom.: 25370 Cov.: 31

Gnomad AFR AF: 0.658

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.548

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.853

Gnomad SAS AF: 0.542

Gnomad FIN AF: 0.572

Gnomad MID AF: 0.563

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.545

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

GnomAD4 genome AF: 0.570 AC: 86678 AN: 151940 Hom.: 25384 Cov.: 31 AF XY: 0.571 AC XY: 42372 AN XY: 74248

Gnomad4 AFR AF: 0.658

Gnomad4 AMR AF: 0.548

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.852

Gnomad4 SAS AF: 0.539

Gnomad4 FIN AF: 0.572

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.544

Alfa AF: 0.516 Hom.: 26428

Bravo AF: 0.576

Asia WGS AF: 0.688 AC: 2389 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	6.9
DANN	Benign	0.32

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: rs2301134; hg19: chr4-90758945;