Genetic Variant SNCA:c.-26+273A>G (chr4-89836689-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000345.4(SNCA):c.-26+273A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.793 in 152,164 control chromosomes in the GnomAD database, including 47,974 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 0.79 ( 47902 hom., cov: 30)

Exomes 𝑓: 0.77 ( 72 hom. )

Consequence

SNCA
NM_000345.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.205

Publications

17 publications found

Variant links:

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 links:

SNCA-AS1 (HGNC:50600): (SNCA antisense RNA 1)

SNCA-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.833 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNCA	NM_000345.4 link	c.-26+273A>G		intron_variant	Intron 1 of 5	ENST00000394991.8	NP_000336.1	P37840-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNCA	ENST00000394991.8 link	c.-26+273A>G		intron_variant	Intron 1 of 5	1	NM_000345.4	ENSP00000378442.4		P37840-1

Frequencies

GnomAD3 genomes

AF:

0.793

AC:

120370

AN:

151824

Hom.:

47855

Cov.:

show subpopulations

Gnomad AFR

AF:

0.812

Gnomad AMI

AF:

0.820

Gnomad AMR

AF:

0.742

Gnomad ASJ

AF:

0.717

Gnomad EAS

AF:

0.855

Gnomad SAS

AF:

0.677

Gnomad FIN

AF:

0.831

Gnomad MID

AF:

0.728

Gnomad NFE

AF:

0.794

Gnomad OTH

AF:

0.784

GnomAD4 exome

AF:

0.775

AC:

172

AN:

222

Hom.:

Cov.:

AF XY:

0.753

AC XY:

128

AN XY:

170

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AF:

1.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

AN:

East Asian (EAS)

AF:

0.833

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.667

AC:

AN:

Middle Eastern (MID)

AF:

1.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.787

AC:

140

AN:

178

Other (OTH)

AF:

0.714

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.793

AC:

120466

AN:

151942

Hom.:

47902

Cov.:

AF XY:

0.791

AC XY:

58712

AN XY:

74254

show subpopulations

African (AFR)

AF:

0.813

AC:

33693

AN:

41454

American (AMR)

AF:

0.742

AC:

11327

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.717

AC:

2486

AN:

3468

East Asian (EAS)

AF:

0.855

AC:

4389

AN:

5136

South Asian (SAS)

AF:

0.676

AC:

3258

AN:

4816

European-Finnish (FIN)

AF:

0.831

AC:

8771

AN:

10556

Middle Eastern (MID)

AF:

0.735

AC:

216

AN:

294

European-Non Finnish (NFE)

AF:

0.794

AC:

53937

AN:

67934

Other (OTH)

AF:

0.781

AC:

1643

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1260

2520

3780

5040

6300

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

868

1736

2604

3472

4340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.796

Hom.:

16357

Bravo

AF:

0.794

Asia WGS

AF:

0.758

AC:

2637

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

8.8

(source)

DANN

Benign

0.61

PhyloP100

-0.20

PromoterAI

-0.029

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over