11-130121668-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3BS2

The NM_001142276.2(APLP2):c.571G>A(p.Gly191Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000963 in 1,613,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00055 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

APLP2
NM_001142276.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 10.0

Publications

4 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when AlphaMissense, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BS2

High AC in GnomAd4 at 83 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142276.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APLP2	NM_001142276.2	MANE Select	c.571G>A	p.Gly191Arg	missense	Exon 5 of 17	NP_001135748.1	Q06481-3
APLP2	NM_001642.3		c.571G>A	p.Gly191Arg	missense	Exon 5 of 18	NP_001633.1	Q06481-1
APLP2	NM_001243299.2		c.601G>A	p.Gly201Arg	missense	Exon 5 of 17	NP_001230228.1	Q06481-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APLP2	ENST00000338167.10	TSL:1 MANE Select	c.571G>A	p.Gly191Arg	missense	Exon 5 of 17	ENSP00000345444.5	Q06481-3
APLP2	ENST00000263574.9	TSL:1	c.571G>A	p.Gly191Arg	missense	Exon 5 of 18	ENSP00000263574.5	Q06481-1
APLP2	ENST00000528499.5	TSL:1	c.571G>A	p.Gly191Arg	missense	Exon 5 of 16	ENSP00000435914.1	Q06481-4

Frequencies

GnomAD3 genomes

AF:

0.000546

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00100

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000593

AC:

149

AN:

251414

AF XY:

0.000581

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00121

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00101

AC:

1471

AN:

1461868

Hom.:

Cov.:

AF XY:

0.000964

AC XY:

701

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.000269

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000131

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00125

AC:

1393

AN:

1111996

Other (OTH)

AF:

0.000960

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

154

232

309

386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

162

216

270

<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:

0.000546

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000458

AC XY:

AN XY:

74284

show subpopulations

African (AFR)

AF:

0.000314

AC:

AN:

41416

American (AMR)

AF:

0.0000655

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00100

AC:

AN:

68030

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

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:

0.000881

Hom.:

Bravo

AF:

0.000525

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00175

AC:

ExAC

AF:

0.000782

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00136

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.79

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.40

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.3

PhyloP100

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.72

Sift

Benign

0.072

Sift4G

Uncertain

0.058

Polyphen

1.0

Vest4

0.71

MutPred

0.88

Gain of catalytic residue at G191 (P = 0.0586)

MVP

0.81

MPC

0.63

ClinPred

0.090

GERP RS

4.7

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.8

Varity_R

0.29

gMVP

0.69

Mutation Taster

=32/68

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over