4-89822180-C-T

Variant names:

• chr4-89822180-C-T
• rs10005233
• NM_000345.4:c.306+66G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 27 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 -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 VariationId 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 rank	MANE	Protein	UniProt
SNCA	NM_000345.4	c.306+66G>A		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+66G>A		intron_variant	Intron 4 of 5	1	NM_000345.4	ENSP00000378442.4

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

GnomAD2 exomes AF: 0.578 AC: 144274 AN: 249630 AF XY: 0.567

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 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

African (AFR) AF: 0.714 AC: 23713 AN: 33202

American (AMR) AF: 0.606 AC: 27109 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.511 AC: 13300 AN: 26034

East Asian (EAS) AF: 0.893 AC: 35376 AN: 39634

South Asian (SAS) AF: 0.545 AC: 46861 AN: 85952

European-Finnish (FIN) AF: 0.575 AC: 30672 AN: 53362

Middle Eastern (MID) AF: 0.588 AC: 3363 AN: 5718

European-Non Finnish (NFE) AF: 0.515 AC: 564128 AN: 1095910

Other (OTH) AF: 0.547 AC: 32709 AN: 59796

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

African (AFR) AF: 0.707 AC: 29301 AN: 41444

American (AMR) AF: 0.556 AC: 8487 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.509 AC: 1767 AN: 3472

East Asian (EAS) AF: 0.852 AC: 4400 AN: 5164

South Asian (SAS) AF: 0.560 AC: 2695 AN: 4814

European-Finnish (FIN) AF: 0.569 AC: 5973 AN: 10506

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.517 AC: 35105 AN: 67924

Other (OTH) AF: 0.564 AC: 1189 AN: 2108

Alfa AF: 0.534 Hom.: 28921

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.3
DANN	Benign	0.79
PhyloP100		-0.98
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: rs10005233; hg19: chr4-90743331;