Genetic Variant AP2A2:p.Lys297Glu (chr11-985509-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_012305.4(AP2A2):c.889A>G(p.Lys297Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K297R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

AP2A2
NM_012305.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.12

Publications

0 publications found

Variant links:

Genes affected

AP2A2 (HGNC:562): (adaptor related protein complex 2 subunit alpha 2) The protein encoded by this gene is a subunit of the AP-2 adaptor protein complex, which is involved in linking lipid and protein membrane components with the clathrin lattice. This interaction supports the formation of clathrin-coated vesicles, and the encoded subunit aids in the process by binding polyphosphoinositide-containing lipids in the cell membrane. [provided by RefSeq, Nov 2016]

AP2A2 Gene-Disease associations (from GenCC):

schizophrenia
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

AP2A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.757

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012305.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP2A2	NM_012305.4	MANE Select	c.889A>G	p.Lys297Glu	missense	Exon 8 of 22	NP_036437.1	O94973-1
AP2A2	NM_001242837.2		c.892A>G	p.Lys298Glu	missense	Exon 8 of 22	NP_001229766.1	O94973-2
AP2A2	NR_144509.2		n.1041A>G		non_coding_transcript_exon	Exon 8 of 21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AP2A2	ENST00000448903.7	TSL:1 MANE Select	c.889A>G	p.Lys297Glu	missense	Exon 8 of 22	ENSP00000413234.3	O94973-1
AP2A2	ENST00000332231.9	TSL:1	c.892A>G	p.Lys298Glu	missense	Exon 8 of 22	ENSP00000327694.5	O94973-2
AP2A2	ENST00000528815.5	TSL:2	n.892A>G		non_coding_transcript_exon	Exon 8 of 21	ENSP00000431630.1	O94973-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.67

MutationAssessor

Pathogenic

3.1

PhyloP100

9.1

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.40

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.021

Polyphen

1.0

Vest4

0.69

MutPred

0.43

Gain of ubiquitination at K298 (P = 0.0221)

MVP

0.66

MPC

1.2

ClinPred

0.92

GERP RS

3.9

PromoterAI

-0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.44

gMVP

0.56

Mutation Taster

=46/54

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over