11-984723-C-A

Variant names:

• chr11-984723-C-A
• NM_012305.4:c.784C>A

Variant summary

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

The NM_012305.4(AP2A2):​c.784C>A​(p.Leu262Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AP2A2 NM_012305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.86

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 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
AP2A2	NM_012305.4	c.784C>A	p.Leu262Met	missense_variant	Exon 7 of 22	ENST00000448903.7	NP_036437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP2A2	ENST00000448903.7	c.784C>A	p.Leu262Met	missense_variant	Exon 7 of 22	1	NM_012305.4	ENSP00000413234.3
AP2A2	ENST00000332231.9	c.784C>A	p.Leu262Met	missense_variant	Exon 7 of 22	1		ENSP00000327694.5
AP2A2	ENST00000528815.5	n.784C>A		non_coding_transcript_exon_variant	Exon 7 of 21	2		ENSP00000431630.1
AP2A2	ENST00000687792.1	n.784C>A		non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000508951.1
AP2A2	ENST00000687890.1	n.784C>A		non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000510756.1
AP2A2	ENST00000693238.1	n.784C>A		non_coding_transcript_exon_variant	Exon 7 of 20			ENSP00000510648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460818 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726752

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.784C>A (p.L262M) alteration is located in exon 7 (coding exon 7) of the AP2A2 gene. This alteration results from a C to A substitution at nucleotide position 784, causing the leucine (L) at amino acid position 262 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	Uncertain	0.39
BayesDel_addAF	Uncertain	0.059	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.059	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.3	M;.;.;M
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0010	D;T;T;D
Sift4G	Benign	0.083	T;T;D;T
Polyphen		1.0	D;.;.;D
Vest4		0.67
MutPred		0.68		Loss of helix (P = 0.079);.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.52
MPC		1.7
ClinPred		0.96	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.46
gMVP		0.50

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: chr11-984723;