15-82659612-A-G

Variant names:

• chr15-82659612-A-G
• NM_001278512.2:c.3254T>C

Variant summary

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

The NM_001278512.2(AP3B2):​c.3254T>C​(p.Met1085Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: 9.08

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP3B2	NM_001278512.2	c.3254T>C	p.Met1085Thr	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.3254T>C	p.Met1085Thr	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

Apr 15, 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 methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1066 of the AP3B2 protein (p.Met1066Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Uncertain	0.54	.;D;D;.;.
Eigen	Benign	0.013
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T;.;T;T;T
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.44	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.6	.;L;L;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	.;D;.;D;D
REVEL	Benign	0.27
Sift	Benign	0.40	.;T;.;T;T
Sift4G	Benign	0.27	.;T;T;T;T
Polyphen		0.012	.;B;B;.;.
Vest4		0.87, 0.88, 0.91, 0.92
MutPred		0.47		.;Gain of methylation at K1065 (P = 0.0394);Gain of methylation at K1065 (P = 0.0394);.;.;
MVP		0.10
MPC		0.050
ClinPred		0.84	D
GERP RS		3.8
Varity_R		0.44
gMVP		0.53

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: chr15-83328364;