11-959468-A-G

Variant names:

• chr11-959468-A-G
• rs1178007291
• NM_012305.4:c.99A>G

Variant summary

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

The NM_012305.4(AP2A2):​c.99A>G​(p.Ile33Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,406,674 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: 0.0000028 (0 hom.)
• Consequence: AP2A2 NM_012305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.18

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.99A>G	p.Ile33Met	missense_variant	Exon 2 of 22	ENST00000448903.7	NP_036437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP2A2	ENST00000448903.7	c.99A>G	p.Ile33Met	missense_variant	Exon 2 of 22	1	NM_012305.4	ENSP00000413234.3
AP2A2	ENST00000332231.9	c.99A>G	p.Ile33Met	missense_variant	Exon 2 of 22	1		ENSP00000327694.5
AP2A2	ENST00000528815.5	n.99A>G		non_coding_transcript_exon_variant	Exon 2 of 21	2		ENSP00000431630.1
AP2A2	ENST00000687792.1	n.99A>G		non_coding_transcript_exon_variant	Exon 2 of 21			ENSP00000508951.1
AP2A2	ENST00000687890.1	n.99A>G		non_coding_transcript_exon_variant	Exon 2 of 21			ENSP00000510756.1
AP2A2	ENST00000693238.1	n.99A>G		non_coding_transcript_exon_variant	Exon 2 of 20			ENSP00000510648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1406674 Hom.: 0 Cov.: 27 AF XY: 0.00000142 AC XY: 1 AN XY: 702534

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: 0.00000375

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.99A>G (p.I33M) alteration is located in exon 2 (coding exon 2) of the AP2A2 gene. This alteration results from a A to G substitution at nucleotide position 99, causing the isoleucine (I) at amino acid position 33 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	0.98
BayesDel_addAF	Uncertain	0.079	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	.;T;T;T;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;.
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.71	D;D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.3	M;.;M;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		0.99	D;.;D;.;.;.
Vest4		0.76
MutPred		0.78		Gain of disorder (P = 0.0637);Gain of disorder (P = 0.0637);Gain of disorder (P = 0.0637);.;.;.;
MVP		0.65
MPC		0.99
ClinPred		0.99	D
GERP RS		3.4
Varity_R		0.77
gMVP		0.68

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: rs1178007291; hg19: chr11-959468; COSMIC: COSV59958086;