Genetic Variant APP:c.2212-10T>C (chr21-25881781-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000484.4(APP):c.2212-10T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,609,616 control chromosomes in the GnomAD database, including 60 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 57 hom. )

Consequence

APP
NM_000484.4 intron

Scores

Splicing: ADA: 0.00001442

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0690

Publications

2 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):

cerebral amyloid angiopathy, APP-related
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Alzheimer disease type 1
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 21-25881781-A-G is Benign according to our data. Variant chr21-25881781-A-G is described in ClinVar as Benign. ClinVar VariationId is 339627.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00135 (204/151618) while in subpopulation EAS AF = 0.0339 (176/5192). AF 95% confidence interval is 0.0298. There are 3 homozygotes in GnomAd4. There are 131 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 204 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000484.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APP	NM_000484.4	MANE Select	c.2212-10T>C	intron	N/A	NP_000475.1	P05067-1
APP	NM_001204301.2		c.2158-10T>C	intron	N/A	NP_001191230.1	P05067-9
APP	NM_201413.3		c.2155-10T>C	intron	N/A	NP_958816.1	P05067-8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
APP	ENST00000346798.8	TSL:1 MANE Select	c.2212-10T>C	intron	N/A	ENSP00000284981.4	P05067-1
APP	ENST00000357903.7	TSL:1	c.2155-10T>C	intron	N/A	ENSP00000350578.3	P05067-8
APP	ENST00000439274.6	TSL:1	c.2044-10T>C	intron	N/A	ENSP00000398879.2	E9PG40

Frequencies

GnomAD3 genomes

AF:

0.00134

AC:

203

AN:

151500

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000244

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0336

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00141

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000883

Gnomad OTH

AF:

0.000483

GnomAD2 exomes

AF:

0.00244

AC:

612

AN:

250812

AF XY:

0.00225

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0289

Gnomad FIN exome

AF:

0.00244

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.00149

AC:

2178

AN:

1457998

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

1092

AN XY:

725474

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33024

American (AMR)

AF:

0.0000224

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.0488

AC:

1934

AN:

39658

South Asian (SAS)

AF:

0.000453

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

52794

Middle Eastern (MID)

AF:

0.000741

AC:

AN:

5398

European-Non Finnish (NFE)

AF:

0.0000505

AC:

AN:

1109964

Other (OTH)

AF:

0.000947

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

126

253

379

506

632

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.00135

AC:

204

AN:

151618

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

131

AN XY:

74142

show subpopulations

African (AFR)

AF:

0.0000244

AC:

AN:

41030

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0339

AC:

176

AN:

5192

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00141

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000884

AC:

AN:

67910

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.000443

Hom.:

Bravo

AF:

0.00128

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alzheimer disease (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

4.9

(source)

DANN

Benign

0.59

PhyloP100

0.069

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000014

dbscSNV1_RF

Benign

0.0040

SpliceAI score (max)

0.050

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over