2-69479040-G-T

Position:

• chr2-69479040-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014911.5(AAK1):​c.2591C>A​(p.Ser864Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AAK1 NM_014911.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.02

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAK1	NM_014911.5	c.2591C>A	p.Ser864Tyr	missense_variant	20/22	ENST00000409085.9	NP_055726.4
AAK1	NM_001371575.1	c.2569+1820C>A		intron_variant			NP_001358504.1
AAK1	NM_001371577.1	c.1981-17329C>A		intron_variant			NP_001358506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAK1	ENST00000409085.9	c.2591C>A	p.Ser864Tyr	missense_variant	20/22	5	NM_014911.5	ENSP00000386456.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Tooth agenesis Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Molecular Biology and Genetics, Acibadem University

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.026	T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.34
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.27		Loss of disorder (P = 0.0323);
MVP		0.88
MPC		1.3
ClinPred		0.97	D
GERP RS		5.9
Varity_R		0.44
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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

Other links and lift over

dbSNP: rs761855107; hg19: chr2-69706172;