rs7577851

Variant names:

• chr2-69496578-C-T
• rs7577851
• NM_014911.5:c.2270-498G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014911.5(AAK1):​c.2270-498G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 151,972 control chromosomes in the GnomAD database, including 9,823 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 0.30 (9823 hom., cov: 31)
• Consequence: AAK1 NM_014911.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.321
• Publications: 18 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014911.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAK1	NM_014911.5	MANE Select	c.2270-498G>A		intron	N/A	NP_055726.4
	AAK1	NM_001426745.1		c.2272+8991G>A		intron	N/A	NP_001413674.1
	AAK1	NM_001426746.1		c.2269+8991G>A		intron	N/A	NP_001413675.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AAK1	ENST00000409085.9	TSL:5 MANE Select	c.2270-498G>A		intron	N/A	ENSP00000386456.3	Q2M2I8-1
	AAK1	ENST00000406297.7	TSL:1	c.2270-498G>A		intron	N/A	ENSP00000385181.3	Q2M2I8-2
	AAK1	ENST00000606389.8	TSL:5	c.2270-498G>A		intron	N/A	ENSP00000485350.2	A0A096LP25

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46248 AN: 151856 Hom.: 9785 Cov.: 31

Gnomad AFR AF: 0.594

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.112

Gnomad EAS AF: 0.278

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.261

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

GnomAD4 genome AF: 0.305 AC: 46340 AN: 151972 Hom.: 9823 Cov.: 31 AF XY: 0.304 AC XY: 22564 AN XY: 74256

African (AFR) AF: 0.594 AC: 24653 AN: 41470

American (AMR) AF: 0.281 AC: 4294 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 388 AN: 3470

East Asian (EAS) AF: 0.278 AC: 1436 AN: 5166

South Asian (SAS) AF: 0.266 AC: 1283 AN: 4818

European-Finnish (FIN) AF: 0.199 AC: 2089 AN: 10508

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11398 AN: 67950

Other (OTH) AF: 0.259 AC: 547 AN: 2110

Alfa AF: 0.213 Hom.: 15565

Bravo AF: 0.326

Asia WGS AF: 0.305 AC: 1061 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.50
PhyloP100		-0.32
Mutation Taster		=100/0	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: rs7577851; hg19: chr2-69723710;