dbSNP rs2619361: SNCA:c.-26+378G>T (chr4-89836584-C-A) – 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+378G>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 152,134 control chromosomes in the GnomAD database, including 3,378 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 ( 3374 hom., cov: 31)

Exomes 𝑓: 0.23 ( 4 hom. )

Consequence

SNCA
NM_000345.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.216

Publications

12 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:

Genome browser will be placed here

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=-0.74).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000345.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SNCA	NM_000345.4	MANE Select	c.-26+378G>T	intron	N/A	NP_000336.1	P37840-1
SNCA	NM_001146054.2		c.-26+159G>T	intron	N/A	NP_001139526.1	P37840-1
SNCA	NM_001146055.2		c.-25-892G>T	intron	N/A	NP_001139527.1	P37840-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SNCA	ENST00000394991.8	TSL:1 MANE Select	c.-26+378G>T	intron	N/A	ENSP00000378442.4	P37840-1
SNCA	ENST00000394986.5	TSL:1	c.-26+159G>T	intron	N/A	ENSP00000378437.1	P37840-1
SNCA	ENST00000394989.6	TSL:1	c.-26+378G>T	intron	N/A	ENSP00000378440.2	P37840-3

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28540

AN:

151886

Hom.:

3373

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0665

Gnomad AMI

AF:

0.350

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.207

Gnomad EAS

AF:

0.000970

Gnomad SAS

AF:

0.121

Gnomad FIN

AF:

0.242

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.271

Gnomad OTH

AF:

0.209

GnomAD4 exome

AF:

0.231

AC:

AN:

130

Hom.:

Cov.:

AF XY:

0.207

AC XY:

AN XY:

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.333

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.500

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.240

AC:

AN:

100

Other (OTH)

AF:

0.125

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.188

AC:

28550

AN:

152004

Hom.:

3374

Cov.:

AF XY:

0.185

AC XY:

13730

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.0663

AC:

2756

AN:

41538

American (AMR)

AF:

0.176

AC:

2693

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

718

AN:

3468

East Asian (EAS)

AF:

0.000972

AC:

AN:

5142

South Asian (SAS)

AF:

0.124

AC:

593

AN:

4794

European-Finnish (FIN)

AF:

0.242

AC:

2557

AN:

10558

Middle Eastern (MID)

AF:

0.146

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.271

AC:

18430

AN:

67920

Other (OTH)

AF:

0.207

AC:

436

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1123

2246

3369

4492

5615

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

298

596

894

1192

1490

<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:

0.231

Hom.:

1741

Bravo

AF:

0.180

Asia WGS

AF:

0.0600

AC:

211

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

7.3

(source)

DANN

Benign

0.71

PhyloP100

0.22

PromoterAI

0.0080

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over