Variant 21-41257148-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012105.5(BACE2):c.1135-10C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,614,068 control chromosomes in the GnomAD database, including 252 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.023 ( 125 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 127 hom. )

Consequence

BACE2
NM_012105.5 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00002271

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.266

Variant links:

Genes affected

BACE2 (HGNC:934): (beta-secretase 2) This gene encodes an integral membrane glycoprotein that functions as an aspartic protease. The encoded protein cleaves amyloid precursor protein into amyloid beta peptide, which is a critical step in the etiology of Alzheimer's disease and Down syndrome. The protein precursor is further processed into an active mature peptide. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

BACE2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP6

Variant 21-41257148-C-T is Benign according to our data. Variant chr21-41257148-C-T is described in ClinVar as [Benign]. Clinvar id is 786689.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
BACE2	NM_012105.5 linkuse as main transcript	c.1135-10C>T	splice_polypyrimidine_tract_variant, intron_variant	ENST00000330333.11
BACE2	NM_138991.3 linkuse as main transcript	c.985-10C>T	splice_polypyrimidine_tract_variant, intron_variant
BACE2	NM_138992.3 linkuse as main transcript	c.1134+6247C>T	intron_variant
BACE2	XM_017028314.2 linkuse as main transcript	c.850-10C>T	splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11 linkuse as main transcript	c.1135-10C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_012105.5	P1	Q9Y5Z0-1

Frequencies

GnomAD3 genomes

AF:

0.0229

AC:

3479

AN:

152138

Hom.:

122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0773

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0129

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000588

Gnomad OTH

AF:

0.0196

GnomAD3 exomes

AF:

0.00660

AC:

1657

AN:

251082

Hom.:

AF XY:

0.00476

AC XY:

646

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.0812

Gnomad AMR exome

AF:

0.00689

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000652

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00272

AC:

3974

AN:

1461812

Hom.:

127

Cov.:

AF XY:

0.00238

AC XY:

1729

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.0800

Gnomad4 AMR exome

AF:

0.00787

Gnomad4 ASJ exome

AF:

0.000421

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000174

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000432

Gnomad4 OTH exome

AF:

0.00677

GnomAD4 genome

AF:

0.0230

AC:

3501

AN:

152256

Hom.:

125

Cov.:

AF XY:

0.0228

AC XY:

1695

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.0776

Gnomad4 AMR

AF:

0.0129

Gnomad4 ASJ

AF:

0.000289

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000588

Gnomad4 OTH

AF:

0.0194

Alfa

AF:

0.0188

Hom.:

Bravo

AF:

0.0254

Asia WGS

AF:

0.00722

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

BACE2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

Cadd

Benign

5.7

Dann

Benign

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000023

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over