rs2736990

Positions:

• chr4-89757390-G-A
• chr4-89757390-G-T

Variant summary

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

The NM_000345.4(SNCA):​c.307-28113C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,028 control chromosomes in the GnomAD database, including 16,473 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 0.45 (16473 hom., cov: 32)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36

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=-0.77).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.542 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNCA	NM_000345.4	c.307-28113C>T		intron_variant		ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.307-28113C>T		intron_variant		1	NM_000345.4	ENSP00000378442	P1

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67962 AN: 151908 Hom.: 16475 Cov.: 32

Gnomad AFR AF: 0.240

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.399

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.450

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

GnomAD4 genome AF: 0.447 AC: 67968 AN: 152028 Hom.: 16473 Cov.: 32 AF XY: 0.448 AC XY: 33277 AN XY: 74318

Gnomad4 AFR AF: 0.240

Gnomad4 AMR AF: 0.495

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.399

Gnomad4 SAS AF: 0.494

Gnomad4 FIN AF: 0.528

Gnomad4 NFE AF: 0.547

Gnomad4 OTH AF: 0.444

Alfa AF: 0.518 Hom.: 46381

Bravo AF: 0.431

Asia WGS AF: 0.395 AC: 1375 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.81

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: rs2736990; hg19: chr4-90678541;