dbSNP rs440446: APOE:c.-24+69C>G (chr19-44905910-C-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBA1

The NM_001302688.2(APOE):c.42C>G(p.Asn14Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.641 in 1,293,628 control chromosomes in the GnomAD database, including 269,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.69 ( 37025 hom., cov: 29)

Exomes 𝑓: 0.63 ( 232051 hom. )

Consequence

APOE
NM_001302688.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:4

Conservation

PhyloP100: -2.66

Publications

112 publications found

Variant links:

Genes affected

APOE (HGNC:613): (apolipoprotein E) The protein encoded by this gene is a major apoprotein of the chylomicron. It binds to a specific liver and peripheral cell receptor, and is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. This gene maps to chromosome 19 in a cluster with the related apolipoprotein C1 and C2 genes. Mutations in this gene result in familial dysbetalipoproteinemia, or type III hyperlipoproteinemia (HLP III), in which increased plasma cholesterol and triglycerides are the consequence of impaired clearance of chylomicron and VLDL remnants. [provided by RefSeq, Jun 2016]

APOE Gene-Disease associations (from GenCC):

Alzheimer disease 2
Inheritance: AD, Unknown Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
hyperlipoproteinemia type 3
Inheritance: AD, AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
lipoprotein glomerulopathy
Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
sea-blue histiocyte syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

APOE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 0.74028 (below the threshold of 3.09). Trascript score misZ: -1.1126 (below the threshold of 3.09). GenCC associations: The gene is linked to hyperlipoproteinemia type 3, sea-blue histiocyte syndrome, lipoprotein glomerulopathy, Alzheimer disease 2.

BP4

Computational evidence support a benign effect (MetaRNN=9.173705E-7).

BP6

Variant 19-44905910-C-G is Benign according to our data. Variant chr19-44905910-C-G is described in ClinVar as Benign. ClinVar VariationId is 1175067.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.85 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001302688.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOE	NM_000041.4	MANE Select	c.-24+69C>G		intron	N/A	NP_000032.1	A0A0S2Z3D5
APOE	NM_001302688.2		c.42C>G	p.Asn14Lys	missense	Exon 1 of 4	NP_001289617.1
APOE	NM_001302691.2		c.-39+69C>G		intron	N/A	NP_001289620.1	A0A0S2Z3D5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
APOE	ENST00000252486.9	TSL:1 MANE Select	c.-24+69C>G		intron	N/A	ENSP00000252486.3	P02649
APOE	ENST00000485628.2	TSL:1	n.46+69C>G		intron	N/A
APOE	ENST00000434152.5	TSL:2	c.42C>G	p.Asn14Lys	missense	Exon 1 of 4	ENSP00000413653.2	H0Y7L5

Frequencies

GnomAD3 genomes

AF:

0.688

AC:

104386

AN:

151714

Hom.:

36967

Cov.:

show subpopulations

Gnomad AFR

AF:

0.857

Gnomad AMI

AF:

0.696

Gnomad AMR

AF:

0.590

Gnomad ASJ

AF:

0.622

Gnomad EAS

AF:

0.407

Gnomad SAS

AF:

0.521

Gnomad FIN

AF:

0.735

Gnomad MID

AF:

0.522

Gnomad NFE

AF:

0.638

Gnomad OTH

AF:

0.652

GnomAD2 exomes

AF:

0.604

AC:

84191

AN:

139394

AF XY:

0.598

show subpopulations

Gnomad AFR exome

AF:

0.863

Gnomad AMR exome

AF:

0.543

Gnomad ASJ exome

AF:

0.629

Gnomad EAS exome

AF:

0.395

Gnomad FIN exome

AF:

0.732

Gnomad NFE exome

AF:

0.635

Gnomad OTH exome

AF:

0.591

GnomAD4 exome

AF:

0.635

AC:

724609

AN:

1141796

Hom.:

232051

Cov.:

AF XY:

0.630

AC XY:

352673

AN XY:

560016

show subpopulations

African (AFR)

AF:

0.864

AC:

20217

AN:

23408

American (AMR)

AF:

0.545

AC:

14335

AN:

26288

Ashkenazi Jewish (ASJ)

AF:

0.628

AC:

9764

AN:

15552

East Asian (EAS)

AF:

0.413

AC:

5063

AN:

12264

South Asian (SAS)

AF:

0.523

AC:

39524

AN:

75558

European-Finnish (FIN)

AF:

0.727

AC:

19828

AN:

27270

Middle Eastern (MID)

AF:

0.556

AC:

1682

AN:

3026

European-Non Finnish (NFE)

AF:

0.642

AC:

589003

AN:

917346

Other (OTH)

AF:

0.613

AC:

25193

AN:

41084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

13483

26967

40450

53934

67417

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18108

36216

54324

72432

90540

<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:

0.688

AC:

104514

AN:

151832

Hom.:

37025

Cov.:

AF XY:

0.688

AC XY:

51042

AN XY:

74182

show subpopulations

African (AFR)

AF:

0.857

AC:

35528

AN:

41440

American (AMR)

AF:

0.590

AC:

9007

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.622

AC:

2158

AN:

3470

East Asian (EAS)

AF:

0.408

AC:

2092

AN:

5126

South Asian (SAS)

AF:

0.521

AC:

2501

AN:

4800

European-Finnish (FIN)

AF:

0.735

AC:

7742

AN:

10540

Middle Eastern (MID)

AF:

0.520

AC:

153

AN:

294

European-Non Finnish (NFE)

AF:

0.638

AC:

43318

AN:

67890

Other (OTH)

AF:

0.656

AC:

1380

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1574

3147

4721

6294

7868

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

800

1600

2400

3200

4000

<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:

0.622

Hom.:

7747

Bravo

AF:

0.684

TwinsUK

AF:

0.654

AC:

2426

ALSPAC

AF:

0.667

AC:

2569

ExAC

AF:

0.542

AC:

10611

Asia WGS

AF:

0.563

AC:

1961

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.77

(source)

DANN

Benign

0.51

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.20

MetaRNN

Benign

9.2e-7

MetaSVM

Benign

-1.0

PhyloP100

-2.7

REVEL

Benign

0.013

ClinPred

0.0024

GERP RS

-3.6

PromoterAI

-0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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