Genetic Variant APBB2:p.Ala279Val (chr4-40945073-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_004307.2(APBB2):c.836C>T(p.Ala279Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000342 in 1,175,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

APBB2
NM_004307.2 missense, splice_region

Scores

Splicing: ADA: 0.4293

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.61

Publications

2 publications found

Variant links:

Genes affected

APBB2 (HGNC:582): (amyloid beta precursor protein binding family B member 2) The protein encoded by this gene interacts with the cytoplasmic domains of amyloid beta (A4) precursor protein and amyloid beta (A4) precursor-like protein 2. This protein contains two phosphotyrosine binding (PTB) domains, which are thought to function in signal transduction. Polymorphisms in this gene have been associated with Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

APBB2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.061093062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APBB2	NM_004307.2 link	c.836C>T	p.Ala279Val	missense_variant, splice_region_variant	Exon 7 of 18	ENST00000508593.6	NP_004298.1	B4DJ88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APBB2	ENST00000508593.6 link	c.836C>T	p.Ala279Val	missense_variant, splice_region_variant	Exon 7 of 18	1	NM_004307.2	ENSP00000427211.1		Q92870-4

Frequencies

GnomAD3 genomes

AF:

0.000213

AC:

AN:

136166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000269

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000754

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00338

Gnomad NFE

AF:

0.000375

Gnomad OTH

AF:

0.00105

GnomAD2 exomes

AF:

0.000283

AC:

AN:

243800

AF XY:

0.000302

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000495

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.000359

AC:

373

AN:

1039588

Hom.:

Cov.:

AF XY:

0.000369

AC XY:

192

AN XY:

519834

show subpopulations

African (AFR)

AF:

0.000251

AC:

AN:

23926

American (AMR)

AF:

0.000325

AC:

AN:

36876

Ashkenazi Jewish (ASJ)

AF:

0.0000566

AC:

AN:

17660

East Asian (EAS)

AF:

0.00

AC:

AN:

21062

South Asian (SAS)

AF:

0.000116

AC:

AN:

77574

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34818

Middle Eastern (MID)

AF:

0.00143

AC:

AN:

4194

European-Non Finnish (NFE)

AF:

0.000402

AC:

315

AN:

783598

Other (OTH)

AF:

0.000602

AC:

AN:

39880

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000213

AC:

AN:

136312

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

65448

show subpopulations

African (AFR)

AF:

0.0000268

AC:

AN:

37282

American (AMR)

AF:

0.0000753

AC:

AN:

13284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3320

East Asian (EAS)

AF:

0.00

AC:

AN:

3914

South Asian (SAS)

AF:

0.00

AC:

AN:

3610

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7874

Middle Eastern (MID)

AF:

0.00362

AC:

AN:

276

European-Non Finnish (NFE)

AF:

0.000375

AC:

AN:

63988

Other (OTH)

AF:

0.00104

AC:

AN:

1922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000412

Hom.:

ESP6500AA

AF:

0.000275

AC:

ESP6500EA

AF:

0.000613

AC:

ExAC

AF:

0.000331

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 15, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.836C>T (p.A279V) alteration is located in exon 7 (coding exon 3) of the APBB2 gene. This alteration results from a C to T substitution at nucleotide position 836, causing the alanine (A) at amino acid position 279 to be replaced by a valine (V). 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

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.56

CADD

Uncertain

(source)

DANN

Uncertain

1.0

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.039

MetaRNN

Benign

0.061

MetaSVM

Benign

-1.1

PhyloP100

7.6

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.55

REVEL

Benign

0.082

Sift

Benign

0.29

Sift4G

Benign

0.17

Vest4

0.34

MVP

0.32

MPC

0.45

ClinPred

0.11

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.15

Mutation Taster

=46/54

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.43

dbscSNV1_RF

Benign

0.29

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: -3

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over