11-985492-A-T

Variant names:

• chr11-985492-A-T
• NM_012305.4:c.872A>T

Variant summary

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

The NM_012305.4(AP2A2):​c.872A>T​(p.Gln291Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: AP2A2 NM_012305.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.12

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2A2	NM_012305.4	c.872A>T	p.Gln291Leu	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.872A>T	p.Gln291Leu	missense_variant	Exon 8 of 22	1	NM_012305.4	ENSP00000413234.3
AP2A2	ENST00000332231.9	c.875A>T	p.Gln292Leu	missense_variant	Exon 8 of 22	1		ENSP00000327694.5
AP2A2	ENST00000528815.5	n.875A>T		non_coding_transcript_exon_variant	Exon 8 of 21	2		ENSP00000431630.1
AP2A2	ENST00000687792.1	n.872A>T		non_coding_transcript_exon_variant	Exon 8 of 21			ENSP00000508951.1
AP2A2	ENST00000687890.1	n.872A>T		non_coding_transcript_exon_variant	Exon 8 of 21			ENSP00000510756.1
AP2A2	ENST00000693238.1	n.872A>T		non_coding_transcript_exon_variant	Exon 8 of 20			ENSP00000510648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.875A>T (p.Q292L) alteration is located in exon 8 (coding exon 8) of the AP2A2 gene. This alteration results from a A to T substitution at nucleotide position 875, causing the glutamine (Q) at amino acid position 292 to be replaced by a leucine (L). 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	Benign	0.25
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	.;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.7	.;.;L
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.30
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.99	D;.;D
Vest4		0.76
MutPred		0.54		.;Gain of catalytic residue at Q291 (P = 0.0016);Gain of catalytic residue at Q291 (P = 0.0016);
MVP		0.73
MPC		0.95
ClinPred		0.95	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.35
gMVP		0.47

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: chr11-985492;