rs10002435

Variant names:

• chr4-89791360-G-A
• rs10002435
• NM_000345.4:c.306+30886C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000345.4(SNCA):​c.306+30886C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 94,198 control chromosomes in the GnomAD database, including 2,932 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 0.27 (2932 hom., cov: 27)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 5 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 Gene-Disease associations (from GenCC):

• autosomal dominant Parkinson disease 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Parkinson disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
• autosomal dominant Parkinson disease 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Lewy body dementia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary late onset Parkinson disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• parkinsonian-pyramidal syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.306+30886C>T		intron_variant	Intron 4 of 5	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.306+30886C>T		intron_variant	Intron 4 of 5	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.274 AC: 25748 AN: 94120 Hom.: 2927 Cov.: 27

Gnomad AFR AF: 0.405

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.246

Gnomad ASJ AF: 0.185

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.252

Gnomad NFE AF: 0.184

Gnomad OTH AF: 0.266

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

GnomAD4 genome AF: 0.274 AC: 25772 AN: 94198 Hom.: 2932 Cov.: 27 AF XY: 0.271 AC XY: 12520 AN XY: 46220

African (AFR) AF: 0.405 AC: 12680 AN: 31292

American (AMR) AF: 0.247 AC: 2493 AN: 10094

Ashkenazi Jewish (ASJ) AF: 0.185 AC: 426 AN: 2300

East Asian (EAS) AF: 0.328 AC: 969 AN: 2956

South Asian (SAS) AF: 0.278 AC: 975 AN: 3510

European-Finnish (FIN) AF: 0.188 AC: 886 AN: 4712

Middle Eastern (MID) AF: 0.260 AC: 51 AN: 196

European-Non Finnish (NFE) AF: 0.184 AC: 6881 AN: 37402

Other (OTH) AF: 0.264 AC: 340 AN: 1288

Alfa AF: 0.121 Hom.: 261

Bravo AF: 0.184

Asia WGS AF: 0.208 AC: 712 AN: 3440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	4.5
DANN	Benign	0.58
PhyloP100		0.0
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: rs10002435; hg19: chr4-90712511;