17-35624397-G-A

Position:

• chr17-35624397-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001030006.2(AP2B1):​c.526G>A​(p.Val176Met) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AP2B1 NM_001030006.2 missense, splice_region
• Scores: Splicing: ADA: 0.9984
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.65

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2B1	NM_001030006.2	c.526G>A	p.Val176Met	missense_variant, splice_region_variant	6/22	ENST00000610402.5	NP_001025177.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2B1	ENST00000610402.5	c.526G>A	p.Val176Met	missense_variant, splice_region_variant	6/22	1	NM_001030006.2	ENSP00000483185.1

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 specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 2024

The c.526G>A (p.V176M) alteration is located in exon 6 (coding exon 5) of the AP2B1 gene. This alteration results from a G to A substitution at nucleotide position 526, causing the valine (V) at amino acid position 176 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	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.63	.;D;.;D;D;.;D;D;.
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D;D;D;D;.;.;.;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;.;H;.;.;H
PrimateAI	Pathogenic	0.83	D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;D;.;.;.;D;.;.;D
Vest4		0.85, 0.75, 0.85
MutPred		0.89		Gain of disorder (P = 0.0994);Gain of disorder (P = 0.0994);.;.;Gain of disorder (P = 0.0994);Gain of disorder (P = 0.0994);Gain of disorder (P = 0.0994);Gain of disorder (P = 0.0994);Gain of disorder (P = 0.0994);
MVP		0.96
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.040		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: chr17-33951416;