15-82659583-C-G

Variant names:

• chr15-82659583-C-G
• NM_001278512.2:c.3283G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278512.2(AP3B2):​c.3283G>C​(p.Val1095Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: AP3B2 NM_001278512.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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]

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

ACMG classification

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=0.076049626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B2	NM_001278512.2	c.3283G>C	p.Val1095Leu	missense_variant	Exon 27 of 27	ENST00000535359.6	NP_001265441.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP3B2	ENST00000535359.6	c.3283G>C	p.Val1095Leu	missense_variant	Exon 27 of 27	1	NM_001278512.2	ENSP00000440984.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant has not been reported in the literature in individuals affected with AP3B2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1076 of the AP3B2 protein (p.Val1076Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	20
DANN	Benign	0.80
DEOGEN2	Benign	0.078	.;T;T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	D;.;D;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.076	T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.23	.;N;N;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.50	.;N;.;N;N
REVEL	Benign	0.043
Sift	Benign	1.0	.;T;.;T;T
Sift4G	Benign	1.0	.;T;T;T;T
Polyphen		0.0010	.;B;B;.;.
Vest4		0.23, 0.12, 0.23, 0.26
MutPred		0.33		.;Loss of MoRF binding (P = 0.1185);Loss of MoRF binding (P = 0.1185);.;.;
MVP		0.34
MPC		0.051
ClinPred		0.56	D
GERP RS		2.1
Varity_R		0.047
gMVP		0.17

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-83328335;