Variant chr11-130122454-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000338167.10(APLP2):c.863C>G(p.Pro288Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

APLP2
ENST00000338167.10 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.42

Variant links:

Genes affected

APLP2 (HGNC:598): (amyloid beta precursor like protein 2) This gene encodes amyloid precursor- like protein 2 (APLP2), which is a member of the APP (amyloid precursor protein) family including APP, APLP1 and APLP2. This protein is ubiquitously expressed. It contains heparin-, copper- and zinc- binding domains at the N-terminus, BPTI/Kunitz inhibitor and E2 domains in the middle region, and transmembrane and intracellular domains at the C-terminus. This protein interacts with major histocompatibility complex (MHC) class I molecules. The synergy of this protein and the APP is required to mediate neuromuscular transmission, spatial learning and synaptic plasticity. This protein has been implicated in the pathogenesis of Alzheimer's disease. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

APLP2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APLP2	NM_001142276.2 linkuse as main transcript	c.863C>G	p.Pro288Arg	missense_variant	6/17	ENST00000338167.10	NP_001135748.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APLP2	ENST00000338167.10 linkuse as main transcript	c.863C>G	p.Pro288Arg	missense_variant	6/17	1	NM_001142276.2	ENSP00000345444	A2	Q06481-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

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

Jun 16, 2024

The c.863C>G (p.P288R) alteration is located in exon 6 (coding exon 6) of the APLP2 gene. This alteration results from a C to G substitution at nucleotide position 863, causing the proline (P) at amino acid position 288 to be replaced by an arginine (R). 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

AlphaMissense

Benign

0.086

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

D;.;D;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.94

.;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.57

D;D;D;D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.55

N;N;N;N;.

MutationTaster

Benign

0.70

D;D;D;D;D;D;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.3

.;N;N;N;N

REVEL

Uncertain

0.49

Sift

Benign

0.25

.;T;D;D;D

Sift4G

Benign

0.30

.;T;T;T;T

Polyphen

0.95

P;D;P;P;.

Vest4

0.51, 0.42, 0.35, 0.35

MutPred

0.29

Loss of catalytic residue at P288 (P = 0.0258);Loss of catalytic residue at P288 (P = 0.0258);Loss of catalytic residue at P288 (P = 0.0258);Loss of catalytic residue at P288 (P = 0.0258);.;

MVP

0.93

MPC

0.52

ClinPred

0.55

GERP RS

5.6

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.090

gMVP

0.26

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over