chr2-69480947-C-G

Position:

• chr2-69480947-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_014911.5(AAK1):​c.2482G>C​(p.Ala828Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000441 in 1,452,236 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: not found (cov: 31)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: AAK1 NM_014911.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2656905).
• BS2: High AC in GnomAdExome4 at 64 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAK1	NM_014911.5	c.2482G>C	p.Ala828Pro	missense_variant	19/22	ENST00000409085.9
AAK1	NM_001371575.1	c.2482G>C	p.Ala828Pro	missense_variant	19/21
AAK1	NM_001371577.1	c.1981-19236G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAK1	ENST00000409085.9	c.2482G>C	p.Ala828Pro	missense_variant	19/22	5	NM_014911.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000441 AC: 64 AN: 1452236 Hom.: 0 Cov.: 30 AF XY: 0.0000430 AC XY: 31 AN XY: 721000

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: 0.0000578

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.2482G>C (p.A828P) alteration is located in exon 19 (coding exon 18) of the AAK1 gene. This alteration results from a G to C substitution at nucleotide position 2482, causing the alanine (A) at amino acid position 828 to be replaced by a proline (P). 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	0.091
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.76	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.11
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.11	T
Polyphen		0.97	D
Vest4		0.25
MutPred		0.30		Gain of loop (P = 0.0013);
MVP		0.46
MPC		0.52
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.33
gMVP		0.21

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: rs1041249379; hg19: chr2-69708079;