Genetic Variant NM_012105.5:c.312+7392A>G (chr21-41175967-A-G) – 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.312+7392A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 152,008 control chromosomes in the GnomAD database, including 5,666 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 0.27 ( 5666 hom., cov: 32)

Exomes 𝑓: 0.083 ( 0 hom. )

Consequence

BACE2
NM_012105.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.407

Publications

11 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:

PLAC4 (HGNC:14616): (placenta enriched 4)

PLAC4 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=-0.89).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
BACE2	NM_012105.5 link	c.312+7392A>G	intron_variant	Intron 1 of 8	ENST00000330333.11	NP_036237.2	Q9Y5Z0-1
PLAC4	NR_148920.1 link	n.9273T>C	non_coding_transcript_exon_variant	Exon 1 of 1
BACE2	NM_138991.3 link	c.312+7392A>G	intron_variant	Intron 1 of 7		NP_620476.1	Q9Y5Z0-2
BACE2	NM_138992.3 link	c.312+7392A>G	intron_variant	Intron 1 of 7		NP_620477.1	Q9Y5Z0-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BACE2	ENST00000330333.11 link	c.312+7392A>G		intron_variant	Intron 1 of 8	1	NM_012105.5	ENSP00000332979.6		Q9Y5Z0-1

Frequencies

GnomAD3 genomes

AF:

0.269

AC:

40791

AN:

151878

Hom.:

5658

Cov.:

show subpopulations

Gnomad AFR

AF:

0.255

Gnomad AMI

AF:

0.263

Gnomad AMR

AF:

0.286

Gnomad ASJ

AF:

0.374

Gnomad EAS

AF:

0.190

Gnomad SAS

AF:

0.328

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.274

Gnomad OTH

AF:

0.288

GnomAD4 exome

AF:

0.0833

AC:

AN:

Hom.:

Cov.:

AF XY:

0.100

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.269

AC:

40849

AN:

151996

Hom.:

5666

Cov.:

AF XY:

0.271

AC XY:

20130

AN XY:

74286

show subpopulations

African (AFR)

AF:

0.255

AC:

10564

AN:

41430

American (AMR)

AF:

0.286

AC:

4371

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.374

AC:

1298

AN:

3466

East Asian (EAS)

AF:

0.190

AC:

981

AN:

5160

South Asian (SAS)

AF:

0.328

AC:

1577

AN:

4806

European-Finnish (FIN)

AF:

0.231

AC:

2441

AN:

10570

Middle Eastern (MID)

AF:

0.463

AC:

136

AN:

294

European-Non Finnish (NFE)

AF:

0.274

AC:

18636

AN:

67976

Other (OTH)

AF:

0.288

AC:

606

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1515

3031

4546

6062

7577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

430

860

1290

1720

2150

<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:

0.277

Hom.:

10141

Bravo

AF:

0.271

Asia WGS

AF:

0.267

AC:

926

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.35

(source)

DANN

Benign

0.48

PhyloP100

-0.41

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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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