rs13427243

Positions:

• chr2-69463055-A-G

Variant summary

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

The NM_014911.5(AAK1):​c.*12814T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 152,104 control chromosomes in the GnomAD database, including 36,738 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 0.68 (36738 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: AAK1 NM_014911.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.130

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AAK1	NM_014911.5	c.*12814T>C		3_prime_UTR_variant	22/22	ENST00000409085.9	NP_055726.4
AAK1	NM_001371575.1	c.*12814T>C		3_prime_UTR_variant	21/21		NP_001358504.1
AAK1	NM_001371577.1	c.1981-1344T>C		intron_variant			NP_001358506.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AAK1	ENST00000409085.9	c.*12814T>C		3_prime_UTR_variant	22/22	5	NM_014911.5	ENSP00000386456
AAK1	ENST00000606389.8	c.*2370T>C		3_prime_UTR_variant	18/18	5		ENSP00000485350	P1
AAK1	ENST00000409068.5	c.1987-1350T>C		intron_variant		2		ENSP00000386342

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103451 AN: 151986 Hom.: 36677 Cov.: 32

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.647

Gnomad FIN AF: 0.607

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.599

Gnomad OTH AF: 0.657

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.681 AC: 103566 AN: 152104 Hom.: 36738 Cov.: 32 AF XY: 0.677 AC XY: 50338 AN XY: 74358

Gnomad4 AFR AF: 0.897

Gnomad4 AMR AF: 0.592

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.645

Gnomad4 FIN AF: 0.607

Gnomad4 NFE AF: 0.599

Gnomad4 OTH AF: 0.662

Alfa AF: 0.643 Hom.: 8309

Bravo AF: 0.688

Asia WGS AF: 0.609 AC: 2120 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.3
DANN	Benign	0.52

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs13427243; hg19: chr2-69690187;