Genetic Variant AAK1:c.*12814T>C (chr2-69463055-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.130

Publications

9 publications found

Variant links:

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]

AAK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AAK1	NM_014911.5	MANE Select	c.*12814T>C	3_prime_UTR	Exon 22 of 22	NP_055726.4
AAK1	NM_001426745.1		c.*2370T>C	3_prime_UTR	Exon 17 of 17	NP_001413674.1
AAK1	NM_001426746.1		c.*2370T>C	3_prime_UTR	Exon 17 of 17	NP_001413675.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
AAK1	ENST00000409085.9	TSL:5 MANE Select	c.*12814T>C	3_prime_UTR	Exon 22 of 22	ENSP00000386456.3
AAK1	ENST00000606389.8	TSL:5	c.*2370T>C	3_prime_UTR	Exon 18 of 18	ENSP00000485350.2
AAK1	ENST00000409068.5	TSL:2	c.1987-1350T>C	intron	N/A	ENSP00000386342.1

Frequencies

GnomAD3 genomes

AF:

0.681

AC:

103451

AN:

151986

Hom.:

36677

Cov.:

show subpopulations

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:

AN:

Hom.:

Cov.:

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.681

AC:

103566

AN:

152104

Hom.:

36738

Cov.:

AF XY:

0.677

AC XY:

50338

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.897

AC:

37243

AN:

41526

American (AMR)

AF:

0.592

AC:

9044

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.690

AC:

2397

AN:

3472

East Asian (EAS)

AF:

0.473

AC:

2441

AN:

5164

South Asian (SAS)

AF:

0.645

AC:

3106

AN:

4816

European-Finnish (FIN)

AF:

0.607

AC:

6413

AN:

10570

Middle Eastern (MID)

AF:

0.619

AC:

182

AN:

294

European-Non Finnish (NFE)

AF:

0.599

AC:

40738

AN:

67960

Other (OTH)

AF:

0.662

AC:

1395

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1565

3130

4696

6261

7826

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

798

1596

2394

3192

3990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.643

Hom.:

12974

Bravo

AF:

0.688

Asia WGS

AF:

0.609

AC:

2120

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

2.3

(source)

DANN

Benign

0.52

PhyloP100

0.13

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over