chr19-49795730-C-T

Position:

chr19-49795730-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_130787.3(AP2A1):c.806C>T(p.Pro269Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00002 in 1,553,374 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: 𝑓 0.000046 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

AP2A1
NM_130787.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.79

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 -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.8

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A1	NM_130787.3 linkuse as main transcript	c.806C>T	p.Pro269Leu	missense_variant	7/23	ENST00000354293.10	NP_570603.2	O95782-2
AP2A1	NM_014203.3 linkuse as main transcript	c.806C>T	p.Pro269Leu	missense_variant	7/24		NP_055018.2	O95782-1
AP2A1	XM_011526556.3 linkuse as main transcript	c.857C>T	p.Pro286Leu	missense_variant	7/24		XP_011524858.1
AP2A1	XM_011526557.4 linkuse as main transcript	c.857C>T	p.Pro286Leu	missense_variant	7/23		XP_011524859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AP2A1	ENST00000354293.10 linkuse as main transcript	c.806C>T	p.Pro269Leu	missense_variant	7/23	1	NM_130787.3	ENSP00000346246.4	O95782-2
AP2A1	ENST00000359032.10 linkuse as main transcript	c.806C>T	p.Pro269Leu	missense_variant	7/24	5		ENSP00000351926.4	O95782-1
AP2A1	ENST00000597774.5 linkuse as main transcript	n.*144C>T		non_coding_transcript_exon_variant	5/22	5		ENSP00000472492.1	M0R2D9
AP2A1	ENST00000597774.5 linkuse as main transcript	n.*144C>T		3_prime_UTR_variant	5/22	5		ENSP00000472492.1	M0R2D9

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00000614

AC:

AN:

162900

Hom.:

AF XY:

0.0000115

AC XY:

AN XY:

86712

show subpopulations

Gnomad AFR exome

AF:

0.000117

Gnomad AMR exome

AF:

0.00

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:

0.0000171

AC:

AN:

1401224

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

692156

show subpopulations

Gnomad4 AFR exome

AF:

0.000220

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000551

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000213

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.0000344

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000145

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:

0.0000387

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.00000877

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

Feb 10, 2022

The c.806C>T (p.P269L) alteration is located in exon 7 (coding exon 7) of the AP2A1 gene. This alteration results from a C to T substitution at nucleotide position 806, causing the proline (P) at amino acid position 269 to be replaced by a leucine (L). 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

0.33

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Benign

-0.66

MutationAssessor

Pathogenic

3.3

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-8.4

D;D

REVEL

Uncertain

0.29

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.91

P;D

Vest4

0.69

MVP

0.65

MPC

2.2

ClinPred

1.0

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.75

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