Variant 21-41168391-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_012105.5(BACE2):c.128T>C(p.Val43Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000791 in 1,263,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.9e-7 ( 0 hom. )

Consequence

BACE2
NM_012105.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.09

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 Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06330216).

BP6

Variant 21-41168391-T-C is Benign according to our data. Variant chr21-41168391-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3259799.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
BACE2	NM_012105.5 linkuse as main transcript	c.128T>C	p.Val43Ala	missense_variant	1/9	ENST00000330333.11	NP_036237.2
BACE2	NM_138991.3 linkuse as main transcript	c.128T>C	p.Val43Ala	missense_variant	1/8		NP_620476.1
BACE2	NM_138992.3 linkuse as main transcript	c.128T>C	p.Val43Ala	missense_variant	1/8		NP_620477.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BACE2	ENST00000330333.11 linkuse as main transcript	c.128T>C	p.Val43Ala	missense_variant	1/9	1	NM_012105.5	ENSP00000332979	P1	Q9Y5Z0-1
BACE2	ENST00000347667.5 linkuse as main transcript	c.128T>C	p.Val43Ala	missense_variant	1/8	1		ENSP00000327528		Q9Y5Z0-2
BACE2	ENST00000328735.10 linkuse as main transcript	c.128T>C	p.Val43Ala	missense_variant	1/8	1		ENSP00000333854		Q9Y5Z0-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.91e-7

AC:

AN:

1263554

Hom.:

Cov.:

AF XY:

0.00000161

AC XY:

AN XY:

620662

show subpopulations

Gnomad4 AFR exome

AF:

0.0000402

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

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.1

DANN

Benign

0.41

DEOGEN2

Benign

0.11

T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0067

LIST_S2

Benign

0.31

T;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.063

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.81

N;N;N

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.25

N;N;N

REVEL

Benign

0.039

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.021

MutPred

0.62

Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);

MVP

0.15

MPC

0.62

ClinPred

0.020

GERP RS

0.70

Varity_R

0.027

gMVP

0.19

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over