Variant chr17-35608295-G-A details in Genebe, Genetics Data Aggregator

Variant summary

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

The ENST00000610402.5(AP2B1):c.433G>A(p.Val145Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,066 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

AP2B1
ENST00000610402.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.89

Variant links:

Genes affected

AP2B1 (HGNC:563): (adaptor related protein complex 2 subunit beta 1) The protein encoded by this gene is one of two large chain components of the assembly protein complex 2, which serves to link clathrin to receptors in coated vesicles. The encoded protein is found on the cytoplasmic face of coated vesicles in the plasma membrane. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

AP2B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.863

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2B1	NM_001030006.2 linkuse as main transcript	c.433G>A	p.Val145Met	missense_variant	5/22	ENST00000610402.5	NP_001025177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2B1	ENST00000610402.5 linkuse as main transcript	c.433G>A	p.Val145Met	missense_variant	5/22	1	NM_001030006.2	ENSP00000483185	P1	P63010-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00000795

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.00

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

Bravo

AF:

0.00000378

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

Aug 28, 2023

The c.433G>A (p.V145M) alteration is located in exon 5 (coding exon 4) of the AP2B1 gene. This alteration results from a G to A substitution at nucleotide position 433, causing the valine (V) at amino acid position 145 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

1.0

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;.;D;.;T;T;.;T;T;.

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.86

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

MetaSVM

Benign

-0.63

MutationAssessor

Pathogenic

3.5

.;.;H;.;.;.;H;.;.;H

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Pathogenic

0.89

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0, 0.99

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

Vest4

0.74, 0.63, 0.73, 0.73

MutPred

0.67

Loss of catalytic residue at V145 (P = 0.0954);Loss of catalytic residue at V145 (P = 0.0954);Loss of catalytic residue at V145 (P = 0.0954);.;.;Loss of catalytic residue at V145 (P = 0.0954);Loss of catalytic residue at V145 (P = 0.0954);Loss of catalytic residue at V145 (P = 0.0954);Loss of catalytic residue at V145 (P = 0.0954);Loss of catalytic residue at V145 (P = 0.0954);

MVP

0.92

ClinPred

0.98

GERP RS

5.4

Varity_R

0.73

gMVP

0.85

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

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