Variant 4-40945073-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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

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:

APBB2 (HGNC:):

APBB2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APBB2	NM_004307.2 linkuse as main transcript	c.836C>T	p.Ala279Val	missense_variant, splice_region_variant	7/18	ENST00000508593.6	NP_004298.1	B4DJ88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APBB2	ENST00000508593.6 linkuse as main transcript	c.836C>T	p.Ala279Val	missense_variant, splice_region_variant	7/18	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

GnomAD3 exomes

AF:

0.000283

AC:

AN:

243800

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

132574

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 SAS exome

AF:

0.0000668

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

Gnomad4 AFR exome

AF:

0.000251

Gnomad4 AMR exome

AF:

0.000325

Gnomad4 ASJ exome

AF:

0.0000566

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000402

Gnomad4 OTH exome

AF:

0.000602

GnomAD4 genome

AF:

0.000213

AC:

AN:

136312

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

AN XY:

65448

show subpopulations

Gnomad4 AFR

AF:

0.0000268

Gnomad4 AMR

AF:

0.0000753

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000375

Gnomad4 OTH

AF:

0.00104

Alfa

AF:

0.000417

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

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

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

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

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

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