Variant 11-972188-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_012305.4(AP2A2):c.406G>A(p.Ala136Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

AP2A2
NM_012305.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.94

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2A2	NM_012305.4 link	c.406G>A	p.Ala136Thr	missense_variant	Exon 4 of 22	ENST00000448903.7	NP_036437.1	O94973-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AP2A2	ENST00000448903.7 link	c.406G>A	p.Ala136Thr	missense_variant	Exon 4 of 22	1	NM_012305.4	ENSP00000413234.3	O94973-1
AP2A2	ENST00000332231.9 link	c.406G>A	p.Ala136Thr	missense_variant	Exon 4 of 22	1		ENSP00000327694.5	O94973-2
AP2A2	ENST00000528815.5 link	n.406G>A		non_coding_transcript_exon_variant	Exon 4 of 21	2		ENSP00000431630.1	O94973-3
AP2A2	ENST00000687792.1 link	n.406G>A		non_coding_transcript_exon_variant	Exon 4 of 21			ENSP00000508951.1	A0A8I5KPP9
AP2A2	ENST00000687890.1 link	n.406G>A		non_coding_transcript_exon_variant	Exon 4 of 21			ENSP00000510756.1	A0A8I5KPP9
AP2A2	ENST00000693238.1 link	n.406G>A		non_coding_transcript_exon_variant	Exon 4 of 20			ENSP00000510648.1	A0A8I5KPP9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000163

AC:

AN:

245560

Hom.:

AF XY:

0.0000224

AC XY:

AN XY:

133666

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000117

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1459898

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726254

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000897

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 19, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.406G>A (p.A136T) alteration is located in exon 4 (coding exon 4) of the AP2A2 gene. This alteration results from a G to A substitution at nucleotide position 406, causing the alanine (A) at amino acid position 136 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

.;T;T;T;.;T;.;.;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;D;D;D;.;.;.;.

M_CAP

Benign

0.011

MetaRNN

Pathogenic

0.81

D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.40

MutationAssessor

Pathogenic

3.2

M;.;M;.;.;.;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-3.3

D;D;D;D;D;D;D;D;D

REVEL

Uncertain

0.46

Sift

Uncertain

0.0010

D;D;D;D;D;D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;D;D;D;D;D;D

Polyphen

1.0

D;.;D;.;.;.;.;.;.

Vest4

0.98

MutPred

0.61

Gain of catalytic residue at A136 (P = 0.0771);Gain of catalytic residue at A136 (P = 0.0771);Gain of catalytic residue at A136 (P = 0.0771);.;.;.;.;.;.;

MVP

0.74

MPC

1.8

ClinPred

0.93

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.66

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over