rs2737012

Variant names:

• chr4-89824556-G-A
• rs2737012
• NM_000345.4:c.164-2168C>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.164-2168C>T 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 152,000 control chromosomes in the GnomAD database, including 3,398 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 (3398 hom., cov: 33)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.689
• Publications: 10 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=-0.83).
• 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 rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.164-2168C>T		intron_variant	Intron 3 of 5	ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.164-2168C>T		intron_variant	Intron 3 of 5	1	NM_000345.4	ENSP00000378442.4

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28552 AN: 151882 Hom.: 3396 Cov.: 33

Gnomad AFR AF: 0.0652

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.122

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.208

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

GnomAD4 genome AF: 0.188 AC: 28562 AN: 152000 Hom.: 3398 Cov.: 33 AF XY: 0.185 AC XY: 13734 AN XY: 74272

African (AFR) AF: 0.0650 AC: 2695 AN: 41470

American (AMR) AF: 0.176 AC: 2686 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3472

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.124 AC: 598 AN: 4822

European-Finnish (FIN) AF: 0.244 AC: 2563 AN: 10508

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

European-Non Finnish (NFE) AF: 0.272 AC: 18500 AN: 67948

Other (OTH) AF: 0.207 AC: 437 AN: 2114

Alfa AF: 0.221 Hom.: 543

Bravo AF: 0.180

Asia WGS AF: 0.0610 AC: 216 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.2
DANN	Benign	0.70
PhyloP100		0.69
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: rs2737012; hg19: chr4-90745707;