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GeneBe

21-41250859-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BA1

The NM_012105.5(BACE2):c.1092C>T(p.Asp364=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,613,088 control chromosomes in the GnomAD database, including 140,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.34 ( 10798 hom., cov: 32)
Exomes 𝑓: 0.41 ( 129602 hom. )

Consequence

BACE2
NM_012105.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.23
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 -15 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=-0.67).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 21-41250859-C-T is Benign according to our data. Variant chr21-41250859-C-T is described in ClinVar as [Benign]. Clinvar id is 3060688.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=-1.23 with no splicing effect.
BA1
?
    BA1 - Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
BACE2NM_012105.5 linkuse as main transcriptc.1092C>T p.Asp364= synonymous_variant 7/9 ENST00000330333.11
BACE2NM_138992.3 linkuse as main transcriptc.1092C>T p.Asp364= synonymous_variant 7/8
BACE2XM_017028314.2 linkuse as main transcriptc.807C>T p.Asp269= synonymous_variant 8/10
BACE2NM_138991.3 linkuse as main transcriptc.984+4796C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
BACE2ENST00000330333.11 linkuse as main transcriptc.1092C>T p.Asp364= synonymous_variant 7/91 NM_012105.5 P1Q9Y5Z0-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.343
AC:
52131
AN:
151974
Hom.:
10794
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.124
Gnomad AMI
AF:
0.404
Gnomad AMR
AF:
0.486
Gnomad ASJ
AF:
0.402
Gnomad EAS
AF:
0.702
Gnomad SAS
AF:
0.544
Gnomad FIN
AF:
0.403
Gnomad MID
AF:
0.459
Gnomad NFE
AF:
0.388
Gnomad OTH
AF:
0.382
GnomAD3 exomes
AF:
0.451
AC:
113307
AN:
251230
Hom.:
27954
AF XY:
0.455
AC XY:
61755
AN XY:
135760
show subpopulations
Gnomad AFR exome
AF:
0.120
Gnomad AMR exome
AF:
0.615
Gnomad ASJ exome
AF:
0.397
Gnomad EAS exome
AF:
0.700
Gnomad SAS exome
AF:
0.553
Gnomad FIN exome
AF:
0.402
Gnomad NFE exome
AF:
0.395
Gnomad OTH exome
AF:
0.443
GnomAD4 exome
AF:
0.411
AC:
600851
AN:
1460996
Hom.:
129602
Cov.:
39
AF XY:
0.415
AC XY:
301943
AN XY:
726868
show subpopulations
Gnomad4 AFR exome
AF:
0.114
Gnomad4 AMR exome
AF:
0.601
Gnomad4 ASJ exome
AF:
0.394
Gnomad4 EAS exome
AF:
0.721
Gnomad4 SAS exome
AF:
0.549
Gnomad4 FIN exome
AF:
0.402
Gnomad4 NFE exome
AF:
0.391
Gnomad4 OTH exome
AF:
0.415
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.343
AC:
52134
AN:
152092
Hom.:
10798
Cov.:
32
AF XY:
0.352
AC XY:
26156
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.123
Gnomad4 AMR
AF:
0.486
Gnomad4 ASJ
AF:
0.402
Gnomad4 EAS
AF:
0.701
Gnomad4 SAS
AF:
0.545
Gnomad4 FIN
AF:
0.403
Gnomad4 NFE
AF:
0.388
Gnomad4 OTH
AF:
0.385
Alfa
AF:
0.387
Hom.:
27261
Bravo
AF:
0.343
Asia WGS
AF:
0.597
AC:
2073
AN:
3478
EpiCase
AF:
0.398
EpiControl
AF:
0.399

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 SciencesOct 30, 2019This 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
-0.67
Cadd
Benign
2.9
Dann
Benign
0.88

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: rs1046210; hg19: chr21-42622786; COSMIC: COSV57737960; COSMIC: COSV57737960; API