2-69496578-C-T

Position:

• chr2-69496578-C-T

Variant summary

Our verdict is Benign. Variant got -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

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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAK1	NM_014911.5	c.2270-498G>A		intron_variant		ENST00000409085.9
AAK1	NM_001371575.1	c.2270-498G>A		intron_variant
AAK1	NM_001371577.1	c.1980+12679G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAK1	ENST00000409085.9	c.2270-498G>A		intron_variant		5	NM_014911.5

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

Gnomad4 AFR AF: 0.594

Gnomad4 AMR AF: 0.281

Gnomad4 ASJ AF: 0.112

Gnomad4 EAS AF: 0.278

Gnomad4 SAS AF: 0.266

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.259

Alfa AF: 0.190 Hom.: 7582

Bravo AF: 0.326

Asia WGS AF: 0.305 AC: 1061 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.50

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: rs7577851; hg19: chr2-69723710;