5-176629528-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003085.5(SNCB):c.121+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.995 in 1,612,646 control chromosomes in the GnomAD database, including 798,971 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.97 ( 72325 hom., cov: 29)

Exomes 𝑓: 1.0 ( 726646 hom. )

Consequence

SNCB
NM_003085.5 splice_region, intron

Scores

Splicing: ADA: 0.04373

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.14

Publications

9 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 links:

MIR4281 (HGNC:38357): (microRNA 4281) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR4281 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 5-176629528-A-G is Benign according to our data. Variant chr5-176629528-A-G is described in ClinVar as Benign. ClinVar VariationId is 1174817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.121+6T>C	splice_region intron	N/A	NP_003076.1	Q16143
SNCB	NM_001001502.3		c.121+6T>C	splice_region intron	N/A	NP_001001502.1	Q16143
SNCB	NM_001363140.2		c.121+6T>C	splice_region 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.121+6T>C	splice_region intron	N/A	ENSP00000377296.2	Q16143
SNCB	ENST00000310112.7	TSL:1	c.121+6T>C	splice_region intron	N/A	ENSP00000308057.3	Q16143
SNCB	ENST00000614675.4	TSL:1	c.121+6T>C	splice_region intron	N/A	ENSP00000479489.1	G4Y816

Frequencies

GnomAD3 genomes

AF:

0.975

AC:

148056

AN:

151884

Hom.:

72273

Cov.:

show subpopulations

Gnomad AFR

AF:

0.913

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.989

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.981

GnomAD2 exomes

AF:

0.994

AC:

243995

AN:

245590

AF XY:

0.995

show subpopulations

Gnomad AFR exome

AF:

0.911

Gnomad AMR exome

AF:

0.996

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.997

GnomAD4 exome

AF:

0.997

AC:

1456831

AN:

1460644

Hom.:

726646

Cov.:

AF XY:

0.998

AC XY:

724988

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.910

AC:

30403

AN:

33426

American (AMR)

AF:

0.995

AC:

44426

AN:

44646

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26051

AN:

26052

East Asian (EAS)

AF:

1.00

AC:

39648

AN:

39648

South Asian (SAS)

AF:

1.00

AC:

86100

AN:

86112

European-Finnish (FIN)

AF:

1.00

AC:

53132

AN:

53132

Middle Eastern (MID)

AF:

0.996

AC:

5745

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111345

AN:

1111542

Other (OTH)

AF:

0.994

AC:

59981

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

183

366

550

733

916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21664

43328

64992

86656

108320

<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:

0.975

AC:

148164

AN:

152002

Hom.:

72325

Cov.:

AF XY:

0.975

AC XY:

72417

AN XY:

74296

show subpopulations

African (AFR)

AF:

0.913

AC:

37813

AN:

41410

American (AMR)

AF:

0.989

AC:

15116

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3470

AN:

3470

East Asian (EAS)

AF:

1.00

AC:

5128

AN:

5128

South Asian (SAS)

AF:

1.00

AC:

4810

AN:

4810

European-Finnish (FIN)

AF:

1.00

AC:

10604

AN:

10604

Middle Eastern (MID)

AF:

1.00

AC:

294

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

67949

AN:

67976

Other (OTH)

AF:

0.981

AC:

2068

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

175

350

525

700

875

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

912

1824

2736

3648

4560

<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:

0.986

Hom.:

39754

Bravo

AF:

0.971

Asia WGS

AF:

0.998

AC:

3471

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Lewy body dementia (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

1.1

PromoterAI

-0.12

Neutral

(source)

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.044

dbscSNV1_RF

Benign

0.32

SpliceAI score (max)

0.010

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