rs2002879

Positions:

• chr2-69510816-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014911.5(AAK1):​c.1777-1356C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 151,944 control chromosomes in the GnomAD database, including 9,578 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 0.33 (9578 hom., cov: 32)
• Consequence: AAK1 NM_014911.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0790

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAK1	NM_014911.5	c.1777-1356C>T		intron_variant		ENST00000409085.9
AAK1	NM_001371575.1	c.1777-1356C>T		intron_variant
AAK1	NM_001371577.1	c.1777-1356C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAK1	ENST00000409085.9	c.1777-1356C>T		intron_variant		5	NM_014911.5
AAK1	ENST00000406297.7	c.1777-1356C>T		intron_variant		1
AAK1	ENST00000409068.5	c.1777-1356C>T		intron_variant		2
AAK1	ENST00000606389.8	c.1777-1356C>T		intron_variant		5		P1

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49801 AN: 151826 Hom.: 9575 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.357

Gnomad EAS AF: 0.524

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.402

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.360

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

GnomAD4 genome AF: 0.328 AC: 49803 AN: 151944 Hom.: 9578 Cov.: 32 AF XY: 0.332 AC XY: 24636 AN XY: 74260

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.429

Gnomad4 ASJ AF: 0.357

Gnomad4 EAS AF: 0.523

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.355

Alfa AF: 0.350 Hom.: 1656

Bravo AF: 0.325

Asia WGS AF: 0.379 AC: 1319 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.60

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: rs2002879; hg19: chr2-69737948;