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GeneBe

21-41168374-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_012105.5(BACE2):c.111G>A(p.Ala37=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000686 in 1,398,120 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0031 ( 3 hom., cov: 31)
Exomes 𝑓: 0.00039 ( 0 hom. )

Consequence

BACE2
NM_012105.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0390
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.74).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 21-41168374-G-A is Benign according to our data. Variant chr21-41168374-G-A is described in ClinVar as [Benign]. Clinvar id is 3048890.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.039 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 3 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BACE2NM_012105.5 linkuse as main transcriptc.111G>A p.Ala37= synonymous_variant 1/9 ENST00000330333.11
BACE2NM_138991.3 linkuse as main transcriptc.111G>A p.Ala37= synonymous_variant 1/8
BACE2NM_138992.3 linkuse as main transcriptc.111G>A p.Ala37= synonymous_variant 1/8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BACE2ENST00000330333.11 linkuse as main transcriptc.111G>A p.Ala37= synonymous_variant 1/91 NM_012105.5 P1Q9Y5Z0-1
BACE2ENST00000347667.5 linkuse as main transcriptc.111G>A p.Ala37= synonymous_variant 1/81 Q9Y5Z0-2
BACE2ENST00000328735.10 linkuse as main transcriptc.111G>A p.Ala37= synonymous_variant 1/81 Q9Y5Z0-3

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00310
AC:
469
AN:
151472
Hom.:
3
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0104
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000789
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00137
Gnomad SAS
AF:
0.000415
Gnomad FIN
AF:
0.000193
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00288
GnomAD3 exomes
AF:
0.000277
AC:
15
AN:
54144
Hom.:
0
AF XY:
0.000284
AC XY:
9
AN XY:
31660
show subpopulations
Gnomad AFR exome
AF:
0.00909
Gnomad AMR exome
AF:
0.000753
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000191
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000158
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000393
AC:
490
AN:
1246542
Hom.:
0
Cov.:
31
AF XY:
0.000381
AC XY:
233
AN XY:
611808
show subpopulations
Gnomad4 AFR exome
AF:
0.00888
Gnomad4 AMR exome
AF:
0.000720
Gnomad4 ASJ exome
AF:
0.0000508
Gnomad4 EAS exome
AF:
0.000110
Gnomad4 SAS exome
AF:
0.000367
Gnomad4 FIN exome
AF:
0.0000471
Gnomad4 NFE exome
AF:
0.000185
Gnomad4 OTH exome
AF:
0.000897
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.00309
AC:
469
AN:
151578
Hom.:
3
Cov.:
31
AF XY:
0.00298
AC XY:
221
AN XY:
74050
show subpopulations
Gnomad4 AFR
AF:
0.0104
Gnomad4 AMR
AF:
0.000788
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00137
Gnomad4 SAS
AF:
0.000416
Gnomad4 FIN
AF:
0.000193
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00285
Alfa
AF:
0.00270
Hom.:
0
Asia WGS
AF:
0.00116
AC:
4
AN:
3452

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

BACE2-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 02, 2020This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.74
Cadd
Benign
7.6
Dann
Benign
0.96

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

LitVar

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

Other links and lift over

dbSNP: rs369963511; hg19: chr21-42540301; API