11-970263-G-A

Position:

• chr11-970263-G-A

Variant summary

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

The NM_012305.4(AP2A2):​c.231G>A​(p.Met77Ile) variant causes a missense 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP2A2 NM_012305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.90

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]

AP2A2 (HGNC:):

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, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A2	NM_012305.4	c.231G>A	p.Met77Ile	missense_variant	3/22	ENST00000448903.7	NP_036437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2A2	ENST00000448903.7	c.231G>A	p.Met77Ile	missense_variant	3/22	1	NM_012305.4	ENSP00000413234.3
AP2A2	ENST00000332231.9	c.231G>A	p.Met77Ile	missense_variant	3/22	1		ENSP00000327694.5
AP2A2	ENST00000528815.5	n.231G>A		non_coding_transcript_exon_variant	3/21	2		ENSP00000431630.1
AP2A2	ENST00000687792.1	n.231G>A		non_coding_transcript_exon_variant	3/21			ENSP00000508951.1
AP2A2	ENST00000687890.1	n.231G>A		non_coding_transcript_exon_variant	3/21			ENSP00000510756.1
AP2A2	ENST00000693238.1	n.231G>A		non_coding_transcript_exon_variant	3/20			ENSP00000510648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

May 24, 2023

The c.231G>A (p.M77I) alteration is located in exon 3 (coding exon 3) of the AP2A2 gene. This alteration results from a G to A substitution at nucleotide position 231, causing the methionine (M) at amino acid position 77 to be replaced by an isoleucine (I). 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	0.97
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	.;T;T;T;.;T;.;.;T
Eigen	Benign	0.083
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.;.;.;.
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;.;L;.;.;.;.;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.32
Sift	Benign	0.043	D;T;D;T;T;T;T;T;T
Sift4G	Uncertain	0.033	D;D;D;D;D;D;T;T;T
Polyphen		0.045	B;.;B;.;.;.;.;.;.
Vest4		0.76
MutPred		0.66		Gain of catalytic residue at L82 (P = 0.0646);Gain of catalytic residue at L82 (P = 0.0646);Gain of catalytic residue at L82 (P = 0.0646);.;.;.;.;.;.;
MVP		0.90
MPC		0.84
ClinPred		0.96	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1306734899; hg19: chr11-970263;