2-69507504-G-A

Position:

• chr2-69507504-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014911.5(AAK1):​c.2081C>T​(p.Thr694Met) variant causes a missense change. The variant allele was found at a frequency of 0.00778 in 1,612,526 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (71 hom.)
• Consequence: AAK1 NM_014911.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.12

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008146942).
• BP6: Variant 2-69507504-G-A is Benign according to our data. Variant chr2-69507504-G-A is described in ClinVar as [Benign]. Clinvar id is 787581.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 771 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AAK1	NM_014911.5	c.2081C>T	p.Thr694Met	missense_variant	15/22	ENST00000409085.9
AAK1	NM_001371575.1	c.2081C>T	p.Thr694Met	missense_variant	15/21
AAK1	NM_001371577.1	c.1980+1753C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AAK1	ENST00000409085.9	c.2081C>T	p.Thr694Met	missense_variant	15/22	5	NM_014911.5

Frequencies

GnomAD3 genomes AF: 0.00507 AC: 772 AN: 152138 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00292

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00920

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00542 AC: 1335 AN: 246418 Hom.: 11 AF XY: 0.00560 AC XY: 748 AN XY: 133598

Gnomad AFR exome AF: 0.00184

Gnomad AMR exome AF: 0.00146

Gnomad ASJ exome AF: 0.00341

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00368

Gnomad NFE exome AF: 0.00963

Gnomad OTH exome AF: 0.00565

GnomAD4 exome AF: 0.00806 AC: 11769 AN: 1460270 Hom.: 71 Cov.: 31 AF XY: 0.00771 AC XY: 5601 AN XY: 726226

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.00372

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00437

Gnomad4 NFE exome AF: 0.00973

Gnomad4 OTH exome AF: 0.00646

GnomAD4 genome AF: 0.00506 AC: 771 AN: 152256 Hom.: 2 Cov.: 32 AF XY: 0.00463 AC XY: 345 AN XY: 74438

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00125

Gnomad4 FIN AF: 0.00292

Gnomad4 NFE AF: 0.00920

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00791 Hom.: 14

Bravo AF: 0.00489

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00105 AC: 4

ESP6500EA AF: 0.00962 AC: 79

ExAC AF: 0.00598 AC: 723

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
MetaRNN	Benign	0.0081	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.52	T
Sift4G	Uncertain	0.019	D;.;D;T;D
Polyphen		1.0, 1.0	.;.;D;D;.
Vest4		0.34, 0.29
MVP		0.49
MPC		1.1
ClinPred		0.028	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.091
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs55889248; hg19: chr2-69734636; COSMIC: COSV101275952;