Variant 11-985531-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_012305.4(AP2A2):c.911C>T(p.Ala304Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000248 in 1,613,946 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

AP2A2
NM_012305.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.73

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A2	NM_012305.4 linkuse as main transcript	c.911C>T	p.Ala304Val	missense_variant	8/22	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.911C>T	p.Ala304Val	missense_variant	8/22	1	NM_012305.4	ENSP00000413234.3	O94973-1
AP2A2	ENST00000332231.9 linkuse as main transcript	c.914C>T	p.Ala305Val	missense_variant	8/22	1		ENSP00000327694.5	O94973-2
AP2A2	ENST00000528815.5 linkuse as main transcript	n.914C>T		non_coding_transcript_exon_variant	8/21	2		ENSP00000431630.1	O94973-3
AP2A2	ENST00000687792.1 linkuse as main transcript	n.911C>T		non_coding_transcript_exon_variant	8/21			ENSP00000508951.1	A0A8I5KPP9
AP2A2	ENST00000687890.1 linkuse as main transcript	n.911C>T		non_coding_transcript_exon_variant	8/21			ENSP00000510756.1	A0A8I5KPP9
AP2A2	ENST00000693238.1 linkuse as main transcript	n.911C>T		non_coding_transcript_exon_variant	8/20			ENSP00000510648.1	A0A8I5KPP9

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000241

AC:

AN:

249062

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135186

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1461682

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727124

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000125

AC:

AN:

152264

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000433

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.000234

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

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

Nov 10, 2024

The c.914C>T (p.A305V) alteration is located in exon 8 (coding exon 8) of the AP2A2 gene. This alteration results from a C to T substitution at nucleotide position 914, causing the alanine (A) at amino acid position 305 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

Pathogenic

0.91

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Uncertain

-0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;T;T

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.024

MetaRNN

Uncertain

0.69

D;D;D

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

.;.;L

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.027

D;T;D

Sift4G

Uncertain

0.034

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.79

MVP

0.62

MPC

1.6

ClinPred

0.62

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.36

gMVP

0.53

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