rs2028535

Positions:

• chr4-89835270-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000345.4(SNCA):​c.121+277C>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 152,098 control chromosomes in the GnomAD database, including 3,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.19 (3400 hom., cov: 33)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.24

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 4-89835270-G-C is Benign according to our data. Variant chr4-89835270-G-C is described in ClinVar as [Benign]. Clinvar id is 1222121.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.121+277C>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.121+277C>G		intron_variant		1	NM_000345.4	ENSP00000378442	P1

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28566 AN: 151980 Hom.: 3399 Cov.: 33

Gnomad AFR AF: 0.0653

Gnomad AMI AF: 0.350

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.243

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: 28575 AN: 152098 Hom.: 3400 Cov.: 33 AF XY: 0.185 AC XY: 13741 AN XY: 74340

Gnomad4 AFR AF: 0.0651

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.207

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.243

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.206

Alfa AF: 0.227 Hom.: 544

Bravo AF: 0.180

Asia WGS AF: 0.0610 AC: 214 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.048
DANN	Benign	0.35

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: rs2028535; hg19: chr4-90756421;