15-82659579-A-G

Position:

chr15-82659579-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001278512.2(AP3B2):c.3287T>C(p.Ile1096Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

AP3B2
NM_001278512.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.86

Variant links:

Genes affected

AP3B2 (HGNC:567): (adaptor related protein complex 3 subunit beta 2) Adaptor protein complex 3 (AP-3 complex) is a heterotrimeric protein complex involved in the formation of clathrin-coated synaptic vesicles. The protein encoded by this gene represents the beta subunit of the neuron-specific AP-3 complex and was first identified as the target antigen in human paraneoplastic neurologic disorders. The encoded subunit binds clathrin and is phosphorylated by a casein kinase-like protein, which mediates synaptic vesicle coat assembly. Defects in this gene are a cause of early-onset epileptic encephalopathy. [provided by RefSeq, Feb 2017]

AP3B2 links:

CPEB1-AS1 (HGNC:27523): (CPEB1 antisense RNA 1)

CPEB1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22985926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP3B2	NM_001278512.2 linkuse as main transcript	c.3287T>C	p.Ile1096Thr	missense_variant	27/27	ENST00000535359.6	NP_001265441.1
CPEB1-AS1	NR_046096.1 linkuse as main transcript	n.1328+9433A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP3B2	ENST00000535359.6 linkuse as main transcript	c.3287T>C	p.Ile1096Thr	missense_variant	27/27	1	NM_001278512.2	ENSP00000440984		Q13367-4
CPEB1-AS1	ENST00000560650.1 linkuse as main transcript	n.1328+9433A>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249192

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135186

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461648

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 03, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 1416568). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1077 of the AP3B2 protein (p.Ile1077Thr). This variant is present in population databases (rs756340733, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AP3B2-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.089

.;T;T;.;.

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.78

T;.;T;T;T

M_CAP

Benign

0.052

MetaRNN

Benign

0.23

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.0

.;L;L;.;.

MutationTaster

Benign

0.70

N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.030

.;N;.;N;N

REVEL

Benign

0.15

Sift

Benign

0.17

.;T;.;T;T

Sift4G

Benign

0.12

.;T;T;T;T

Polyphen

0.0

.;B;B;.;.

Vest4

0.11, 0.079, 0.17, 0.20

MutPred

0.55

.;Gain of disorder (P = 0.0216);Gain of disorder (P = 0.0216);.;.;

MVP

0.15

MPC

0.068

ClinPred

0.58

GERP RS

2.7

Varity_R

0.031

gMVP

0.11

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