rs10014396

Variant names:

• chr4-89791478-T-C
• rs10014396
• NM_000345.4:c.306+30768A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-89791478-T-C
• chr4-89791478-T-G

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+30768A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 150,710 control chromosomes in the GnomAD database, including 2,921 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 0.17 (2921 hom., cov: 29)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.379
• Publications: 8 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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.306+30768A>G		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+30768A>G		intron_variant	Intron 4 of 5	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.172 AC: 25898 AN: 150600 Hom.: 2915 Cov.: 29

Gnomad AFR AF: 0.310

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.0959

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.164

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

GnomAD4 genome AF: 0.172 AC: 25930 AN: 150710 Hom.: 2921 Cov.: 29 AF XY: 0.172 AC XY: 12633 AN XY: 73592

African (AFR) AF: 0.310 AC: 12665 AN: 40860

American (AMR) AF: 0.167 AC: 2528 AN: 15170

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 427 AN: 3468

East Asian (EAS) AF: 0.189 AC: 966 AN: 5100

South Asian (SAS) AF: 0.205 AC: 981 AN: 4778

European-Finnish (FIN) AF: 0.0959 AC: 985 AN: 10268

Middle Eastern (MID) AF: 0.177 AC: 51 AN: 288

European-Non Finnish (NFE) AF: 0.102 AC: 6914 AN: 67770

Other (OTH) AF: 0.163 AC: 342 AN: 2096

Alfa AF: 0.130 Hom.: 4050

Bravo AF: 0.184

Asia WGS AF: 0.211 AC: 729 AN: 3472

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.4
DANN	Benign	0.37
PhyloP100		-0.38
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: rs10014396; hg19: chr4-90712629;