Genetic Variant APBA2:p.Ser144Trp (chr15-29054315-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001353788.2(APBA2):c.431C>G(p.Ser144Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S144L) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APBA2
NM_001353788.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.90

Publications

0 publications found

Variant links:

Genes affected

APBA2 (HGNC:579): (amyloid beta precursor protein binding family A member 2) The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adapter protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilizes APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion. [provided by RefSeq, Jul 2017]

APBA2 Gene-Disease associations (from GenCC):

epilepsy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

APBA2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13973397).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353788.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APBA2	NM_001353788.2	MANE Select	c.431C>G	p.Ser144Trp	missense	Exon 4 of 15	NP_001340717.1	Q99767-1
APBA2	NM_001353789.2		c.431C>G	p.Ser144Trp	missense	Exon 4 of 15	NP_001340718.1	Q99767-1
APBA2	NM_001353790.2		c.431C>G	p.Ser144Trp	missense	Exon 4 of 15	NP_001340719.1	Q99767-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APBA2	ENST00000683413.1	MANE Select	c.431C>G	p.Ser144Trp	missense	Exon 4 of 15	ENSP00000507394.1	Q99767-1
APBA2	ENST00000558259.5	TSL:1	c.431C>G	p.Ser144Trp	missense	Exon 3 of 14	ENSP00000454171.1	Q99767-1
APBA2	ENST00000411764.5	TSL:1	c.431C>G	p.Ser144Trp	missense	Exon 3 of 13	ENSP00000409312.1	Q99767-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53306

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111980

Other (OTH)

AF:

0.00

AC:

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.84

M_CAP

Benign

0.046

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

PhyloP100

1.9

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-1.5

REVEL

Benign

0.14

Sift

Benign

0.046

Sift4G

Benign

0.11

Polyphen

0.96

Vest4

0.44

MutPred

0.21

Loss of glycosylation at S144 (P = 0.0043)

MVP

0.61

MPC

0.58

ClinPred

0.17

GERP RS

4.3

Varity_R

0.068

gMVP

0.18

Mutation Taster

=95/5

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over