rs12987661

Variant names:

• chr2-69586326-T-C
• rs12987661
• NM_014911.5:c.164-29348A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_014911.5(AAK1):​c.164-29348A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 152,094 control chromosomes in the GnomAD database, including 934 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.11 (934 hom., cov: 32)
• Consequence: AAK1 NM_014911.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.92
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AAK1	NM_014911.5	c.164-29348A>G		intron_variant	Intron 2 of 21	ENST00000409085.9	NP_055726.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AAK1	ENST00000409085.9	c.164-29348A>G		intron_variant	Intron 2 of 21	5	NM_014911.5	ENSP00000386456.3

Frequencies

GnomAD3 genomes AF: 0.105 AC: 16009 AN: 151976 Hom.: 934 Cov.: 32

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.134

Gnomad AMR AF: 0.0550

Gnomad ASJ AF: 0.0727

Gnomad EAS AF: 0.0435

Gnomad SAS AF: 0.0944

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0887

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.105 AC: 16020 AN: 152094 Hom.: 934 Cov.: 32 AF XY: 0.104 AC XY: 7762 AN XY: 74340

African (AFR) AF: 0.110 AC: 4548 AN: 41468

American (AMR) AF: 0.0548 AC: 838 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0727 AC: 252 AN: 3468

East Asian (EAS) AF: 0.0438 AC: 227 AN: 5184

South Asian (SAS) AF: 0.0949 AC: 457 AN: 4816

European-Finnish (FIN) AF: 0.141 AC: 1485 AN: 10562

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.116 AC: 7879 AN: 68006

Other (OTH) AF: 0.0887 AC: 187 AN: 2108

Alfa AF: 0.110 Hom.: 3117

Bravo AF: 0.0986

Asia WGS AF: 0.0670 AC: 236 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	21
DANN	Benign	0.85
PhyloP100		1.9
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12987661; hg19: chr2-69813458;