Variant 19-49793001-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_130787.3(AP2A1):c.614C>T(p.Thr205Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000069 in 1,449,316 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: 32)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

AP2A1
NM_130787.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.64

Variant links:

Genes affected

AP2A1 (HGNC:561): (adaptor related protein complex 2 subunit alpha 1) This gene encodes the alpha 1 adaptin subunit of the adaptor protein 2 (AP-2) complex found in clathrin coated vesicles. The AP-2 complex is a heterotetramer consisting of two large adaptins (alpha or beta), a medium adaptin (mu), and a small adaptin (sigma). The complex is part of the protein coat on the cytoplasmic face of coated vesicles which links clathrin to receptors in vesicles. Alternative splicing of this gene results in two transcript variants encoding two different isoforms. A third transcript variant has been described, but its full length nature has not been determined. [provided by RefSeq, Jul 2008]

AP2A1 links:

AP2A1 (HGNC:):

AP2A1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A1	NM_130787.3 linkuse as main transcript	c.614C>T	p.Thr205Met	missense_variant	6/23	ENST00000354293.10	NP_570603.2	O95782-2
AP2A1	NM_014203.3 linkuse as main transcript	c.614C>T	p.Thr205Met	missense_variant	6/24		NP_055018.2	O95782-1
AP2A1	XM_011526556.3 linkuse as main transcript	c.665C>T	p.Thr222Met	missense_variant	6/24		XP_011524858.1
AP2A1	XM_011526557.4 linkuse as main transcript	c.665C>T	p.Thr222Met	missense_variant	6/23		XP_011524859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AP2A1	ENST00000354293.10 linkuse as main transcript	c.614C>T	p.Thr205Met	missense_variant	6/23	1	NM_130787.3	ENSP00000346246.4	O95782-2
AP2A1	ENST00000359032.10 linkuse as main transcript	c.614C>T	p.Thr205Met	missense_variant	6/24	5		ENSP00000351926.4	O95782-1
AP2A1	ENST00000597774.5 linkuse as main transcript	n.158-35C>T		intron_variant		5		ENSP00000472492.1	M0R2D9
AP2A1	ENST00000600199.1 linkuse as main transcript	n.741C>T		non_coding_transcript_exon_variant	6/8	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000874

AC:

AN:

228820

Hom.:

AF XY:

0.0000161

AC XY:

AN XY:

124116

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000358

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000971

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000690

AC:

AN:

1449316

Hom.:

Cov.:

AF XY:

0.00000695

AC XY:

AN XY:

719704

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000233

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000119

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000723

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000827

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

Jun 01, 2023

The c.614C>T (p.T205M) alteration is located in exon 6 (coding exon 6) of the AP2A1 gene. This alteration results from a C to T substitution at nucleotide position 614, causing the threonine (T) at amino acid position 205 to be replaced by a methionine (M). 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

0.71

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.42

.;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Uncertain

0.089

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Benign

-0.77

MutationAssessor

Uncertain

2.2

M;M

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.3

D;D

REVEL

Uncertain

0.47

Sift

Benign

0.19

T;T

Sift4G

Benign

0.19

T;T

Polyphen

1.0

D;D

Vest4

0.93

MutPred

0.73

Loss of catalytic residue at T205 (P = 0.0258);Loss of catalytic residue at T205 (P = 0.0258);

MVP

0.71

MPC

2.3

ClinPred

0.98

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.51

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