dbSNP rs2830008: APP:c.865+2696A>G (chr21-26019144-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000484.4(APP):c.865+2696A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 152,214 control chromosomes in the GnomAD database, including 3,413 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.21 ( 3413 hom., cov: 33)

Consequence

APP
NM_000484.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.57

Publications

5 publications found

Variant links:

Genes affected

APP (HGNC:620): (amyloid beta precursor protein) This gene encodes a cell surface receptor and transmembrane precursor protein that is cleaved by secretases to form a number of peptides. Some of these peptides are secreted and can bind to the acetyltransferase complex APBB1/TIP60 to promote transcriptional activation, while others form the protein basis of the amyloid plaques found in the brains of patients with Alzheimer disease. In addition, two of the peptides are antimicrobial peptides, having been shown to have bacteriocidal and antifungal activities. Mutations in this gene have been implicated in autosomal dominant Alzheimer disease and cerebroarterial amyloidosis (cerebral amyloid angiopathy). Multiple transcript variants encoding several different isoforms have been found for this gene. [provided by RefSeq, Aug 2014]

APP Gene-Disease associations (from GenCC):

Alzheimer disease type 1
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
cerebral amyloid angiopathy, APP-related
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
ABeta amyloidosis, Arctic type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, dutch type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, Iowa type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABeta amyloidosis, Italian type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABetaA21G amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
ABetaL34V amyloidosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
early-onset autosomal dominant Alzheimer disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

APP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APP	NM_000484.4 link	c.865+2696A>G		intron_variant	Intron 6 of 17	ENST00000346798.8	NP_000475.1	P05067-1A0A140VJC8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APP	ENST00000346798.8 link	c.865+2696A>G		intron_variant	Intron 6 of 17	1	NM_000484.4	ENSP00000284981.4		P05067-1

Frequencies

GnomAD3 genomes

AF:

0.208

AC:

31624

AN:

152096

Hom.:

3418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.160

Gnomad AMI

AF:

0.128

Gnomad AMR

AF:

0.242

Gnomad ASJ

AF:

0.241

Gnomad EAS

AF:

0.120

Gnomad SAS

AF:

0.274

Gnomad FIN

AF:

0.252

Gnomad MID

AF:

0.231

Gnomad NFE

AF:

0.224

Gnomad OTH

AF:

0.205

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.208

AC:

31625

AN:

152214

Hom.:

3413

Cov.:

AF XY:

0.208

AC XY:

15518

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.160

AC:

6648

AN:

41538

American (AMR)

AF:

0.242

AC:

3707

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.241

AC:

835

AN:

3470

East Asian (EAS)

AF:

0.119

AC:

617

AN:

5174

South Asian (SAS)

AF:

0.273

AC:

1319

AN:

4830

European-Finnish (FIN)

AF:

0.252

AC:

2670

AN:

10600

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.224

AC:

15214

AN:

67982

Other (OTH)

AF:

0.203

AC:

429

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1279

2557

3836

5114

6393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

346

692

1038

1384

1730

<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:

0.218

Hom.:

11648

Bravo

AF:

0.201

Asia WGS

AF:

0.195

AC:

678

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.093

(source)

DANN

Benign

0.66

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over