Variant chr2-69507504-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_014911.5(AAK1):c.2081C>T(p.Thr694Met) variant causes a missense change. The variant allele was found at a frequency of 0.00778 in 1,612,526 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0051 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0081 ( 71 hom. )

Consequence

AAK1
NM_014911.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.12

Variant links:

Genes affected

AAK1 (HGNC:19679): (AP2 associated kinase 1) This gene encodes a member of the SNF1 subfamily of serine/threonine protein kinases. Adaptor-related protein complex 2 (AP-2 complexes) functions during receptor-mediated endocytosis to trigger clathrin assembly, interact with membrane-bound receptors, and recruit encodytic accessory factors. The encoded protein interacts with and phosphorylates a subunit of the AP-2 complex, which promotes binding of AP-2 to sorting signals found in membrane-bound receptors and subsequent receptor endocytosis. Its kinase activity is stimulated by clathrin. This kinase has been shown to play an important role in regulating the clathrin-mediated endocytosis of the rabies virus, facilitating infection. Inhibitors of this kinase are being studied as candidate therapeutics to disrupt the entry of viruses, including SARS-CoV-2, into target cells. It is also involved in positive regulation of Notch pathway signaling in mammals. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Aug 2020]

AAK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008146942).

BP6

Variant 2-69507504-G-A is Benign according to our data. Variant chr2-69507504-G-A is described in ClinVar as [Benign]. Clinvar id is 787581.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 771 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAK1	NM_014911.5 link	c.2081C>T	p.Thr694Met	missense_variant	15/22	ENST00000409085.9	NP_055726.4	Q2M2I8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAK1	ENST00000409085.9 link	c.2081C>T	p.Thr694Met	missense_variant	15/22	5	NM_014911.5	ENSP00000386456.3		Q2M2I8-1

Frequencies

GnomAD3 genomes

AF:

0.00507

AC:

772

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00292

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00920

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00542

AC:

1335

AN:

246418

Hom.:

AF XY:

0.00560

AC XY:

748

AN XY:

133598

show subpopulations

Gnomad AFR exome

AF:

0.00184

Gnomad AMR exome

AF:

0.00146

Gnomad ASJ exome

AF:

0.00341

Gnomad EAS exome

AF:

0.0000561

Gnomad SAS exome

AF:

0.00110

Gnomad FIN exome

AF:

0.00368

Gnomad NFE exome

AF:

0.00963

Gnomad OTH exome

AF:

0.00565

GnomAD4 exome

AF:

0.00806

AC:

11769

AN:

1460270

Hom.:

Cov.:

AF XY:

0.00771

AC XY:

5601

AN XY:

726226

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00153

Gnomad4 ASJ exome

AF:

0.00372

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00125

Gnomad4 FIN exome

AF:

0.00437

Gnomad4 NFE exome

AF:

0.00973

Gnomad4 OTH exome

AF:

0.00646

GnomAD4 genome

AF:

0.00506

AC:

771

AN:

152256

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

345

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00125

Gnomad4 FIN

AF:

0.00292

Gnomad4 NFE

AF:

0.00920

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00791

Hom.:

Bravo

AF:

0.00489

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0125

AC:

ESP6500AA

AF:

0.00105

AC:

ESP6500EA

AF:

0.00962

AC:

ExAC

AF:

0.00598

AC:

723

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 16, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

.;.;T;.;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

D;D;D;D;D

MetaRNN

Benign

0.0081

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

.;.;M;M;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.2

.;.;N;N;.

REVEL

Benign

0.19

Sift

Uncertain

0.0020

.;.;D;D;.

Sift4G

Uncertain

0.019

D;.;D;T;D

Polyphen

1.0, 1.0

.;.;D;D;.

Vest4

0.34, 0.29

MVP

0.49

MPC

1.1

ClinPred

0.028

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.091

gMVP

0.21

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over