Genetic Variant SNCB:c.282+59_282+62dupACAC (chr5-176626335-G-GGTGT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_003085.5(SNCB):c.282+59_282+62dupACAC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 864,220 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

SNCB
NM_003085.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.463

Publications

2 publications found

Variant links:

Genes affected

SNCB (HGNC:11140): (synuclein beta) This gene encodes a member of a small family of proteins that inhibit phospholipase D2 and may function in neuronal plasticity. The encoded protein is abundant in lesions of patients with Alzheimer disease. A mutation in this gene was found in individuals with dementia with Lewy bodies. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

SNCB Gene-Disease associations (from GenCC):

Lewy body dementia
Inheritance: Unknown, AD Classification: MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics

SNCB links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 7 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003085.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SNCB	NM_003085.5	MANE Select	c.282+59_282+62dupACAC	intron	N/A	NP_003076.1	Q16143
SNCB	NM_001001502.3		c.282+59_282+62dupACAC	intron	N/A	NP_001001502.1	Q16143
SNCB	NM_001363140.2		c.282+59_282+62dupACAC	intron	N/A	NP_001350069.1	Q16143

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
SNCB	ENST00000393693.7	TSL:1 MANE Select	c.282+62_282+63insACAC	intron	N/A	ENSP00000377296.2	Q16143
SNCB	ENST00000310112.7	TSL:1	c.282+62_282+63insACAC	intron	N/A	ENSP00000308057.3	Q16143
SNCB	ENST00000614675.4	TSL:1	c.240+62_240+63insACAC	intron	N/A	ENSP00000479489.1	G4Y816

Frequencies

GnomAD3 genomes

AF:

0.0000469

AC:

AN:

149346

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000124

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000978

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000149

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000112

AC:

AN:

714874

Hom.:

AF XY:

0.0000104

AC XY:

AN XY:

383282

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000521

AC:

AN:

19212

American (AMR)

AF:

0.00

AC:

AN:

43154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21070

East Asian (EAS)

AF:

0.000176

AC:

AN:

34146

South Asian (SAS)

AF:

0.0000141

AC:

AN:

70694

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47468

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

440914

Other (OTH)

AF:

0.00

AC:

AN:

35452

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.319

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:

0.0000469

AC:

AN:

149346

Hom.:

Cov.:

AF XY:

0.0000412

AC XY:

AN XY:

72776

show subpopulations

African (AFR)

AF:

0.000124

AC:

AN:

40430

American (AMR)

AF:

0.00

AC:

AN:

14978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5022

South Asian (SAS)

AF:

0.00

AC:

AN:

4692

European-Finnish (FIN)

AF:

0.0000978

AC:

AN:

10224

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000149

AC:

AN:

67296

Other (OTH)

AF:

0.00

AC:

AN:

2058

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

664

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.46

Splicing

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