4-89836243-G-C

Position:

• chr4-89836243-G-C

Variant summary

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

The ENST00000394991.8(SNCA):​c.-25-551C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 154,764 control chromosomes in the GnomAD database, including 27,236 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 0.58 (26805 hom., cov: 31)
  • Exomes 𝑓: 0.51 (431 hom.)
• Consequence: SNCA ENST00000394991.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.937

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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNCA	NM_000345.4	c.-25-551C>G		intron_variant		ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.-25-551C>G		intron_variant		1	NM_000345.4	ENSP00000378442	P1

Frequencies

GnomAD3 genomes AF: 0.584 AC: 88701 AN: 151760 Hom.: 26784 Cov.: 31

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.862

Gnomad SAS AF: 0.543

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.574

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.558

GnomAD4 exome AF: 0.509 AC: 1468 AN: 2884 Hom.: 431 Cov.: 0 AF XY: 0.526 AC XY: 858 AN XY: 1630

Gnomad4 AFR exome AF: 0.611

Gnomad4 AMR exome AF: 0.577

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.921

Gnomad4 SAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.526

Gnomad4 NFE exome AF: 0.472

Gnomad4 OTH exome AF: 0.569

GnomAD4 genome AF: 0.584 AC: 88766 AN: 151880 Hom.: 26805 Cov.: 31 AF XY: 0.585 AC XY: 43388 AN XY: 74190

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.499

Gnomad4 EAS AF: 0.862

Gnomad4 SAS AF: 0.540

Gnomad4 FIN AF: 0.573

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.556

Alfa AF: 0.388 Hom.: 967

Bravo AF: 0.592

Asia WGS AF: 0.689 AC: 2392 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.23
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3756063; hg19: chr4-90757394;