2-69507505-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_014911.5(AAK1):ā€‹c.2080A>Gā€‹(p.Thr694Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T694M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000048 ( 0 hom. )

Consequence

AAK1
NM_014911.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13716394).
BS2
High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AAK1NM_014911.5 linkuse as main transcriptc.2080A>G p.Thr694Ala missense_variant 15/22 ENST00000409085.9 NP_055726.4 Q2M2I8-1
AAK1NM_001371575.1 linkuse as main transcriptc.2080A>G p.Thr694Ala missense_variant 15/21 NP_001358504.1
AAK1NM_001371577.1 linkuse as main transcriptc.1980+1752A>G intron_variant NP_001358506.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AAK1ENST00000409085.9 linkuse as main transcriptc.2080A>G p.Thr694Ala missense_variant 15/225 NM_014911.5 ENSP00000386456.3 Q2M2I8-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000406
AC:
1
AN:
246514
Hom.:
0
AF XY:
0.00000748
AC XY:
1
AN XY:
133642
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000894
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460374
Hom.:
0
Cov.:
31
AF XY:
0.00000826
AC XY:
6
AN XY:
726290
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 12, 2024The c.2080A>G (p.T694A) alteration is located in exon 15 (coding exon 14) of the AAK1 gene. This alteration results from a A to G substitution at nucleotide position 2080, causing the threonine (T) at amino acid position 694 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Benign
-0.51
CADD
Benign
22
DANN
Uncertain
0.97
DEOGEN2
Benign
0.016
.;.;T;.;T
Eigen
Benign
-0.15
Eigen_PC
Benign
0.00063
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Benign
0.67
T;T;T;T;T
M_CAP
Benign
0.0099
T
MetaRNN
Benign
0.14
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
.;.;L;L;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-0.10
.;.;N;N;.
REVEL
Benign
0.028
Sift
Benign
0.36
.;.;T;T;.
Sift4G
Benign
0.15
T;.;T;T;T
Polyphen
0.025, 0.66
.;.;B;P;.
Vest4
0.12, 0.078
MutPred
0.29
.;.;Gain of catalytic residue at T694 (P = 0.0077);Gain of catalytic residue at T694 (P = 0.0077);.;
MVP
0.60
MPC
0.92
ClinPred
0.29
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.047
gMVP
0.17

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

LitVar

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

Other links and lift over

dbSNP: rs1396420658; hg19: chr2-69734637; API