Genetic Variant BACE2:c.*1806C>T (chr21-41277430-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_012105.5(BACE2):c.*1806C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.71 in 152,038 control chromosomes in the GnomAD database, including 38,868 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.71 ( 38862 hom., cov: 31)

Exomes 𝑓: 0.88 ( 6 hom. )

Consequence

BACE2
NM_012105.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.962

Publications

3 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.964 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
BACE2	NM_012105.5 link	c.*1806C>T	3_prime_UTR_variant	Exon 9 of 9	ENST00000330333.11	NP_036237.2	Q9Y5Z0-1
BACE2	NM_138991.3 link	c.*1806C>T	3_prime_UTR_variant	Exon 8 of 8		NP_620476.1	Q9Y5Z0-2
BACE2	NM_138992.3 link	c.*2003C>T	3_prime_UTR_variant	Exon 8 of 8		NP_620477.1	Q9Y5Z0-3
BACE2	XM_017028314.2 link	c.*1806C>T	3_prime_UTR_variant	Exon 10 of 10		XP_016883803.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BACE2	ENST00000330333.11 link	c.*1806C>T		3_prime_UTR_variant	Exon 9 of 9	1	NM_012105.5	ENSP00000332979.6		Q9Y5Z0-1
BACE2	ENST00000347667.5 link	c.*1806C>T		3_prime_UTR_variant	Exon 8 of 8	1		ENSP00000327528.4		Q9Y5Z0-2

Frequencies

GnomAD3 genomes

AF:

0.710

AC:

107812

AN:

151902

Hom.:

38841

Cov.:

show subpopulations

Gnomad AFR

AF:

0.603

Gnomad AMI

AF:

0.693

Gnomad AMR

AF:

0.815

Gnomad ASJ

AF:

0.737

Gnomad EAS

AF:

0.987

Gnomad SAS

AF:

0.836

Gnomad FIN

AF:

0.677

Gnomad MID

AF:

0.782

Gnomad NFE

AF:

0.724

Gnomad OTH

AF:

0.746

GnomAD4 exome

AF:

0.875

AC:

AN:

Hom.:

Cov.:

AF XY:

0.800

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.900

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.710

AC:

107882

AN:

152022

Hom.:

38862

Cov.:

AF XY:

0.716

AC XY:

53196

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.602

AC:

24966

AN:

41438

American (AMR)

AF:

0.815

AC:

12467

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.737

AC:

2555

AN:

3468

East Asian (EAS)

AF:

0.987

AC:

5087

AN:

5154

South Asian (SAS)

AF:

0.835

AC:

4022

AN:

4818

European-Finnish (FIN)

AF:

0.677

AC:

7146

AN:

10556

Middle Eastern (MID)

AF:

0.779

AC:

229

AN:

294

European-Non Finnish (NFE)

AF:

0.724

AC:

49201

AN:

67982

Other (OTH)

AF:

0.748

AC:

1578

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1584

3167

4751

6334

7918

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

840

1680

2520

3360

4200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.730

Hom.:

49358

Bravo

AF:

0.715

Asia WGS

AF:

0.901

AC:

3130

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.40

(source)

DANN

Benign

0.67

PhyloP100

-0.96

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over