chr4-89837896-G-T

Variant names:

• chr4-89837896-G-T
• rs2619363
• NM_001146055.2:c.-26+356C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_001146055.2(SNCA):​c.-26+356C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 151,788 control chromosomes in the GnomAD database, including 3,333 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 (3333 hom., cov: 30)
• Consequence: SNCA NM_001146055.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.505
• Publications: 23 publications found

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:50600): (SNCA antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_001146055.2	c.-26+356C>A		intron_variant	Intron 1 of 5		NP_001139527.1
SNCA	NM_001375285.1	c.-95+356C>A		intron_variant	Intron 1 of 6		NP_001362214.1
SNCA-AS1	NR_045481.1	n.335-365G>T		intron_variant	Intron 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000336904.7	c.-26+356C>A		intron_variant	Intron 1 of 5	2		ENSP00000338345.3
SNCA-AS1	ENST00000501215.1	n.312-365G>T		intron_variant	Intron 1 of 1	2
SNCA-AS1	ENST00000513653.1	n.328-365G>T		intron_variant	Intron 1 of 3	3

Frequencies

GnomAD3 genomes AF: 0.186 AC: 28278 AN: 151670 Hom.: 3332 Cov.: 30

Gnomad AFR AF: 0.0646

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.206

Gnomad EAS AF: 0.000970

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.208

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

GnomAD4 genome AF: 0.186 AC: 28287 AN: 151788 Hom.: 3333 Cov.: 30 AF XY: 0.184 AC XY: 13632 AN XY: 74196

African (AFR) AF: 0.0644 AC: 2666 AN: 41406

American (AMR) AF: 0.177 AC: 2697 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.206 AC: 712 AN: 3462

East Asian (EAS) AF: 0.000972 AC: 5 AN: 5142

South Asian (SAS) AF: 0.124 AC: 597 AN: 4812

European-Finnish (FIN) AF: 0.243 AC: 2553 AN: 10514

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18256 AN: 67888

Other (OTH) AF: 0.206 AC: 433 AN: 2102

Alfa AF: 0.199 Hom.: 1351

Bravo AF: 0.179

Asia WGS AF: 0.0590 AC: 210 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	16
DANN	Benign	0.91
PhyloP100		0.51
PromoterAI		-0.016	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2619363; hg19: chr4-90759047;