chr11-984724-T-G

Position:

• chr11-984724-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_012305.4(AP2A2):​c.785T>G​(p.Leu262Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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: 7.87

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A2	NM_012305.4	c.785T>G	p.Leu262Arg	missense_variant	7/22	ENST00000448903.7	NP_036437.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP2A2	ENST00000448903.7	c.785T>G	p.Leu262Arg	missense_variant	7/22	1	NM_012305.4	ENSP00000413234.3
AP2A2	ENST00000332231.9	c.785T>G	p.Leu262Arg	missense_variant	7/22	1		ENSP00000327694.5
AP2A2	ENST00000528815.5	n.785T>G		non_coding_transcript_exon_variant	7/21	2		ENSP00000431630.1
AP2A2	ENST00000687792.1	n.785T>G		non_coding_transcript_exon_variant	7/21			ENSP00000508951.1
AP2A2	ENST00000687890.1	n.785T>G		non_coding_transcript_exon_variant	7/21			ENSP00000510756.1
AP2A2	ENST00000693238.1	n.785T>G		non_coding_transcript_exon_variant	7/20			ENSP00000510648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460676 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726676

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 23, 2024

The c.785T>G (p.L262R) alteration is located in exon 7 (coding exon 7) of the AP2A2 gene. This alteration results from a T to G substitution at nucleotide position 785, causing the leucine (L) at amino acid position 262 to be replaced by an arginine (R). 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	1.0
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	.;.;T;D
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Pathogenic	3.4	M;.;.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.1	D;D;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.96
MutPred		0.88		Loss of ubiquitination at K260 (P = 0.0595);.;Loss of ubiquitination at K260 (P = 0.0595);Loss of ubiquitination at K260 (P = 0.0595);
MVP		0.83
MPC		2.2
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.92
gMVP		0.92

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: chr11-984724;