Variant 21-41168454-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012105.5(BACE2):c.191T>A(p.Leu64Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BACE2
NM_012105.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12207806).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
BACE2	NM_012105.5 linkuse as main transcript	c.191T>A	p.Leu64Gln	missense_variant	1/9	ENST00000330333.11
BACE2	NM_138991.3 linkuse as main transcript	c.191T>A	p.Leu64Gln	missense_variant	1/8
BACE2	NM_138992.3 linkuse as main transcript	c.191T>A	p.Leu64Gln	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BACE2	ENST00000330333.11 linkuse as main transcript	c.191T>A	p.Leu64Gln	missense_variant	1/9	1	NM_012105.5	P1	Q9Y5Z0-1
BACE2	ENST00000347667.5 linkuse as main transcript	c.191T>A	p.Leu64Gln	missense_variant	1/8	1			Q9Y5Z0-2
BACE2	ENST00000328735.10 linkuse as main transcript	c.191T>A	p.Leu64Gln	missense_variant	1/8	1			Q9Y5Z0-3

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151656

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1246182

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

612048

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151656

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74044

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 2022

The c.191T>A (p.L64Q) alteration is located in exon 1 (coding exon 1) of the BACE2 gene. This alteration results from a T to A substitution at nucleotide position 191, causing the leucine (L) at amino acid position 64 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

Cadd

Pathogenic

Dann

Benign

0.92

DEOGEN2

Benign

0.13

T;.;.

Eigen

Benign

-0.94

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.73

T;T;T

M_CAP

Pathogenic

0.40

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;L;L

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.020

N;N;N

REVEL

Benign

0.027

Sift

Benign

0.29

T;T;T

Sift4G

Benign

0.15

T;T;T

Polyphen

0.010

B;B;B

Vest4

0.19

MutPred

0.50

Gain of solvent accessibility (P = 0.0044);Gain of solvent accessibility (P = 0.0044);Gain of solvent accessibility (P = 0.0044);

MVP

0.16

MPC

1.5

ClinPred

0.34

GERP RS

1.3

Varity_R

0.17

gMVP

0.48

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.

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