chr11-959457-A-G

Position:

chr11-959457-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The ENST00000448903.7(AP2A2):c.88A>G(p.Ile30Val) variant causes a missense change. The variant allele was found at a frequency of 0.000392 in 1,552,142 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. I30L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00040 ( 1 hom. )

Consequence

AP2A2
ENST00000448903.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.99

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:

AP2A2 (HGNC:):

AP2A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08664763).

BS2

High AC in GnomAd4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A2	NM_012305.4 linkuse as main transcript	c.88A>G	p.Ile30Val	missense_variant	2/22	ENST00000448903.7	NP_036437.1	O94973-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AP2A2	ENST00000448903.7 linkuse as main transcript	c.88A>G	p.Ile30Val	missense_variant	2/22	1	NM_012305.4	ENSP00000413234.3	O94973-1
AP2A2	ENST00000332231.9 linkuse as main transcript	c.88A>G	p.Ile30Val	missense_variant	2/22	1		ENSP00000327694.5	O94973-2
AP2A2	ENST00000528815.5 linkuse as main transcript	n.88A>G		non_coding_transcript_exon_variant	2/21	2		ENSP00000431630.1	O94973-3
AP2A2	ENST00000687792.1 linkuse as main transcript	n.88A>G		non_coding_transcript_exon_variant	2/21			ENSP00000508951.1	A0A8I5KPP9
AP2A2	ENST00000687890.1 linkuse as main transcript	n.88A>G		non_coding_transcript_exon_variant	2/21			ENSP00000510756.1	A0A8I5KPP9
AP2A2	ENST00000693238.1 linkuse as main transcript	n.88A>G		non_coding_transcript_exon_variant	2/20			ENSP00000510648.1	A0A8I5KPP9

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000500

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000318

AC:

AN:

241812

Hom.:

AF XY:

0.000350

AC XY:

AN XY:

131478

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000566

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:

0.000522

Gnomad OTH exome

AF:

0.000169

GnomAD4 exome

AF:

0.000401

AC:

561

AN:

1399868

Hom.:

Cov.:

AF XY:

0.000412

AC XY:

288

AN XY:

699428

show subpopulations

Gnomad4 AFR exome

AF:

0.0000949

Gnomad4 AMR exome

AF:

0.000501

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:

0.000484

Gnomad4 OTH exome

AF:

0.000412

GnomAD4 genome

AF:

0.000309

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000500

Gnomad4 OTH

AF:

0.00143

Alfa

AF:

0.000479

Hom.:

Bravo

AF:

0.000491

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000279

AC:

ESP6500EA

AF:

0.000246

AC:

ExAC

AF:

0.000298

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 26, 2024

The c.88A>G (p.I30V) alteration is located in exon 2 (coding exon 2) of the AP2A2 gene. This alteration results from a A to G substitution at nucleotide position 88, causing the isoleucine (I) at amino acid position 30 to be replaced by a valine (V). 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

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.22

.;T;T;T;.;T

Eigen

Benign

-0.093

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D;D;D;D;.

M_CAP

Benign

0.0092

MetaRNN

Benign

0.087

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;.;N;.;.;.

MutationTaster

Benign

0.99

D;D;D;N

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.28

N;N;N;N;N;N

REVEL

Benign

0.032

Sift

Benign

1.0

T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T

Polyphen

0.0020

B;.;B;.;.;.

Vest4

0.24

MVP

0.34

MPC

0.63

ClinPred

0.035

GERP RS

4.5

Varity_R

0.069

gMVP

0.090

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