Genetic Variant SNCA:c.-26+268G>A (chr4-89836694-C-T) – 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+268G>A 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 152,164 control chromosomes in the GnomAD database, including 3,376 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 ( 3367 hom., cov: 31)

Exomes 𝑓: 0.29 ( 9 hom. )

Consequence

SNCA
NM_000345.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.400

Publications

8 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=-0.78).

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
SNCA	NM_000345.4	MANE Select	c.-26+268G>A	intron	N/A	NP_000336.1
SNCA-AS1	NR_045481.1		n.294C>T	non_coding_transcript_exon	Exon 1 of 4
SNCA	NM_001146054.2		c.-26+49G>A	intron	N/A	NP_001139526.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
SNCA	ENST00000394991.8	TSL:1 MANE Select	c.-26+268G>A	intron	N/A	ENSP00000378442.4
SNCA	ENST00000394986.5	TSL:1	c.-26+49G>A	intron	N/A	ENSP00000378437.1
SNCA	ENST00000394989.6	TSL:1	c.-26+268G>A	intron	N/A	ENSP00000378440.2

Frequencies

GnomAD3 genomes

AF:

0.188

AC:

28499

AN:

151896

Hom.:

3366

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0662

Gnomad AMI

AF:

0.348

Gnomad AMR

AF:

0.177

Gnomad ASJ

AF:

0.207

Gnomad EAS

AF:

0.000965

Gnomad SAS

AF:

0.122

Gnomad FIN

AF:

0.243

Gnomad MID

AF:

0.140

Gnomad NFE

AF:

0.271

Gnomad OTH

AF:

0.206

GnomAD4 exome

AF:

0.287

AC:

AN:

150

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

116

show subpopulations

African (AFR)

AF:

0.250

AC:

AN:

American (AMR)

AF:

0.500

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

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:

0.317

AC:

AN:

120

Other (OTH)

AF:

0.100

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

28509

AN:

152014

Hom.:

3367

Cov.:

AF XY:

0.185

AC XY:

13725

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0660

AC:

2740

AN:

41508

American (AMR)

AF:

0.176

AC:

2692

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

718

AN:

3470

East Asian (EAS)

AF:

0.000967

AC:

AN:

5172

South Asian (SAS)

AF:

0.124

AC:

597

AN:

4812

European-Finnish (FIN)

AF:

0.243

AC:

2557

AN:

10544

Middle Eastern (MID)

AF:

0.144

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.271

AC:

18410

AN:

67922

Other (OTH)

AF:

0.205

AC:

431

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1068

2137

3205

4274

5342

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:

0.190

Hom.:

794

Bravo

AF:

0.180

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

3.8

(source)

DANN

Benign

0.88

PhyloP100

-0.40

PromoterAI

-0.018

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over