2-69495988-G-A
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_014911.5(AAK1):c.2362C>T(p.Pro788Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000548 in 1,550,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000055 ( 0 hom. )
Consequence
AAK1
NM_014911.5 missense
NM_014911.5 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 4.07
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.06461802).
BS2
High AC in GnomAd4 at 8 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000626 AC: 10AN: 159718Hom.: 0 AF XY: 0.0000238 AC XY: 2AN XY: 84112
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GnomAD4 exome AF: 0.0000551 AC: 77AN: 1398330Hom.: 0 Cov.: 30 AF XY: 0.0000493 AC XY: 34AN XY: 689942
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GnomAD4 genome AF: 0.0000526 AC: 8AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74300
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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 submitter | clinical testing | Ambry Genetics | Sep 16, 2021 | The c.2362C>T (p.P788S) alteration is located in exon 17 (coding exon 16) of the AAK1 gene. This alteration results from a C to T substitution at nucleotide position 2362, causing the proline (P) at amino acid position 788 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;N;N
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N
REVEL
Benign
Sift
Pathogenic
.;D;D
Sift4G
Benign
T;T;T
Polyphen
0.058, 1.0
.;B;D
Vest4
0.21, 0.38
MVP
MPC
1.1
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at