11-959468-A-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012305.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2A2	NM_012305.4	MANE Select	c.99A>G	p.Ile33Met	missense	Exon 2 of 22	NP_036437.1	O94973-1
	AP2A2	NM_001242837.2		c.99A>G	p.Ile33Met	missense	Exon 2 of 22	NP_001229766.1	O94973-2
	AP2A2	NR_144509.2		n.251A>G		non_coding_transcript_exon	Exon 2 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AP2A2	ENST00000448903.7	TSL:1 MANE Select	c.99A>G	p.Ile33Met	missense	Exon 2 of 22	ENSP00000413234.3	O94973-1
	AP2A2	ENST00000332231.9	TSL:1	c.99A>G	p.Ile33Met	missense	Exon 2 of 22	ENSP00000327694.5	O94973-2
	AP2A2	ENST00000528815.5	TSL:2	n.99A>G		non_coding_transcript_exon	Exon 2 of 21	ENSP00000431630.1	O94973-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 244008 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31856

American (AMR) AF: 0.00 AC: 0 AN: 42522

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25632

East Asian (EAS) AF: 0.00 AC: 0 AN: 39370

South Asian (SAS) AF: 0.00 AC: 0 AN: 84106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00000375 AC: 4 AN: 1065824

Other (OTH) AF: 0.00 AC: 0 AN: 58506

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00383038), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.053	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		2.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.76
MutPred		0.78		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
Mutation Taster		=41/59	disease causing

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

Other links and lift over

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