rs1057519271

chr15-82663148-TGTGA-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001278512.2(AP3B2):c.2579_2582del(p.Leu860GlnfsTer10) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000206 in 1,459,534 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AP3B2 NM_001278512.2 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.36

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 Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-82663148-TGTGA-T is Pathogenic according to our data. Variant chr15-82663148-TGTGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 374849.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AP3B2	NM_001278512.2	c.2579_2582del	p.Leu860GlnfsTer10	frameshift_variant	22/27	ENST00000535359.6
CPEB1-AS1	NR_046096.1	n.1328+13006_1328+13009del		intron_variant, non_coding_transcript_variant
AP3B2	NM_001278511.2	c.2426_2429del	p.Leu809GlnfsTer10	frameshift_variant	20/25
AP3B2	NM_004644.5	c.2522_2525del	p.Leu841GlnfsTer10	frameshift_variant	21/26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP3B2	ENST00000535359.6	c.2579_2582del	p.Leu860GlnfsTer10	frameshift_variant	22/27	1	NM_001278512.2
CPEB1-AS1	ENST00000560650.1	n.1328+13006_1328+13009del		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000808 AC: 2 AN: 247438 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134280

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: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459534 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725956

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Developmental and epileptic encephalopathy, 48 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1057519271; hg19: chr15-83331900;