4-89822180-C-T

Position:

• chr4-89822180-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000345.4(SNCA):​c.306+66G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.543 in 1,596,208 control chromosomes in the GnomAD database, including 241,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27192 hom., cov: 32)
  • Exomes 𝑓: 0.54 (213813 hom.)
• Consequence: SNCA NM_000345.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.983

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-89822180-C-T is Benign according to our data. Variant chr4-89822180-C-T is described in ClinVar as [Benign]. Clinvar id is 1296756.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.831 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNCA	NM_000345.4	c.306+66G>A		intron_variant		ENST00000394991.8	NP_000336.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8	c.306+66G>A		intron_variant		1	NM_000345.4	ENSP00000378442	P1

Frequencies

GnomAD3 genomes AF: 0.589 AC: 89448 AN: 151776 Hom.: 27168 Cov.: 32

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.467

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.509

Gnomad EAS AF: 0.852

Gnomad SAS AF: 0.562

Gnomad FIN AF: 0.569

Gnomad MID AF: 0.585

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.566

GnomAD3 exomes AF: 0.578 AC: 144274 AN: 249630 Hom.: 42988 AF XY: 0.567 AC XY: 76522 AN XY: 135022

Gnomad AFR exome AF: 0.716

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.505

Gnomad EAS exome AF: 0.851

Gnomad SAS exome AF: 0.550

Gnomad FIN exome AF: 0.579

Gnomad NFE exome AF: 0.517

Gnomad OTH exome AF: 0.547

GnomAD4 exome AF: 0.538 AC: 777231 AN: 1444314 Hom.: 213813 Cov.: 28 AF XY: 0.537 AC XY: 386459 AN XY: 719776

Gnomad4 AFR exome AF: 0.714

Gnomad4 AMR exome AF: 0.606

Gnomad4 ASJ exome AF: 0.511

Gnomad4 EAS exome AF: 0.893

Gnomad4 SAS exome AF: 0.545

Gnomad4 FIN exome AF: 0.575

Gnomad4 NFE exome AF: 0.515

Gnomad4 OTH exome AF: 0.547

GnomAD4 genome AF: 0.589 AC: 89515 AN: 151894 Hom.: 27192 Cov.: 32 AF XY: 0.589 AC XY: 43746 AN XY: 74220

Gnomad4 AFR AF: 0.707

Gnomad4 AMR AF: 0.556

Gnomad4 ASJ AF: 0.509

Gnomad4 EAS AF: 0.852

Gnomad4 SAS AF: 0.560

Gnomad4 FIN AF: 0.569

Gnomad4 NFE AF: 0.517

Gnomad4 OTH AF: 0.564

Alfa AF: 0.525 Hom.: 17439

Bravo AF: 0.597

Asia WGS AF: 0.694 AC: 2410 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs10005233; hg19: chr4-90743331;