19-49795730-C-A

Variant names:

• chr19-49795730-C-A
• NM_130787.3:c.806C>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_130787.3(AP2A1):​c.806C>A​(p.Pro269Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,224 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: AP2A1 NM_130787.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.79

Genes affected

AP2A1 (HGNC:561): (adaptor related protein complex 2 subunit alpha 1) This gene encodes the alpha 1 adaptin subunit of the adaptor protein 2 (AP-2) complex found in clathrin coated vesicles. The AP-2 complex is a heterotetramer consisting of two large adaptins (alpha or beta), a medium adaptin (mu), and a small adaptin (sigma). The complex is part of the protein coat on the cytoplasmic face of coated vesicles which links clathrin to receptors in vesicles. Alternative splicing of this gene results in two transcript variants encoding two different isoforms. A third transcript variant has been described, but its full length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2A1	NM_130787.3	c.806C>A	p.Pro269Gln	missense_variant	Exon 7 of 23	ENST00000354293.10	NP_570603.2
AP2A1	NM_014203.3	c.806C>A	p.Pro269Gln	missense_variant	Exon 7 of 24		NP_055018.2
AP2A1	XM_011526556.3	c.857C>A	p.Pro286Gln	missense_variant	Exon 7 of 24		XP_011524858.1
AP2A1	XM_011526557.4	c.857C>A	p.Pro286Gln	missense_variant	Exon 7 of 23		XP_011524859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP2A1	ENST00000354293.10	c.806C>A	p.Pro269Gln	missense_variant	Exon 7 of 23	1	NM_130787.3	ENSP00000346246.4
AP2A1	ENST00000359032.10	c.806C>A	p.Pro269Gln	missense_variant	Exon 7 of 24	5		ENSP00000351926.4
AP2A1	ENST00000597774.5	n.*144C>A		non_coding_transcript_exon_variant	Exon 5 of 22	5		ENSP00000472492.1
AP2A1	ENST00000597774.5	n.*144C>A		3_prime_UTR_variant	Exon 5 of 22	5		ENSP00000472492.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.14e-7 AC: 1 AN: 1401224 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 692156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000276

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.45	.;T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.7	D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.96	D;D
Vest4		0.67
MutPred		0.49		Loss of catalytic residue at P269 (P = 0.012);Loss of catalytic residue at P269 (P = 0.012);
MVP		0.58
MPC		2.3
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.75

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: chr19-50298987;