chr11-985453-G-A

Variant names:

• chr11-985453-G-A
• rs768056290
• NM_012305.4:c.833G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_012305.4(AP2A2):​c.833G>A​(p.Arg278His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,640 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R278L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: AP2A2 NM_012305.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.78

Genes affected

AP2A2 (HGNC:562): (adaptor related protein complex 2 subunit alpha 2) The protein encoded by this gene is a subunit of the AP-2 adaptor protein complex, which is involved in linking lipid and protein membrane components with the clathrin lattice. This interaction supports the formation of clathrin-coated vesicles, and the encoded subunit aids in the process by binding polyphosphoinositide-containing lipids in the cell membrane. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.773
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2A2	NM_012305.4	c.833G>A	p.Arg278His	missense_variant	Exon 8 of 22	ENST00000448903.7	NP_036437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP2A2	ENST00000448903.7	c.833G>A	p.Arg278His	missense_variant	Exon 8 of 22	1	NM_012305.4	ENSP00000413234.3
AP2A2	ENST00000332231.9	c.836G>A	p.Arg279His	missense_variant	Exon 8 of 22	1		ENSP00000327694.5
AP2A2	ENST00000528815.5	n.836G>A		non_coding_transcript_exon_variant	Exon 8 of 21	2		ENSP00000431630.1
AP2A2	ENST00000687792.1	n.833G>A		non_coding_transcript_exon_variant	Exon 8 of 21			ENSP00000508951.1
AP2A2	ENST00000687890.1	n.833G>A		non_coding_transcript_exon_variant	Exon 8 of 21			ENSP00000510756.1
AP2A2	ENST00000693238.1	n.833G>A		non_coding_transcript_exon_variant	Exon 8 of 20			ENSP00000510648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248126 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134738

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461640 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727092

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000826 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Uncertain	0.034	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.28	.;.;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Benign	0.035	D
MetaRNN	Pathogenic	0.77	D;D;D;D
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.3	.;.;.;M
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D;D;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.043	D;D;D;D
Sift4G	Benign	0.11	T;D;D;T
Polyphen		1.0	D;.;.;D
Vest4		0.86
MutPred		0.56		.;.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.64
MPC		2.0
ClinPred		0.98	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.55

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

LitVar

Other links and lift over

dbSNP: rs768056290; hg19: chr11-985453; COSMIC: COSV59962025; COSMIC: COSV59962025;