Variant 11-984724-T-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AP2A2
NM_012305.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.87

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
AP2A2	NM_012305.4 link	c.785T>G	p.Leu262Arg	missense_variant	Exon 7 of 22	ENST00000448903.7	NP_036437.1	O94973-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
AP2A2	ENST00000448903.7 link	c.785T>G	p.Leu262Arg	missense_variant	Exon 7 of 22	1	NM_012305.4	ENSP00000413234.3	O94973-1
AP2A2	ENST00000332231.9 link	c.785T>G	p.Leu262Arg	missense_variant	Exon 7 of 22	1		ENSP00000327694.5	O94973-2
AP2A2	ENST00000528815.5 link	n.785T>G		non_coding_transcript_exon_variant	Exon 7 of 21	2		ENSP00000431630.1	O94973-3
AP2A2	ENST00000687792.1 link	n.785T>G		non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000508951.1	A0A8I5KPP9
AP2A2	ENST00000687890.1 link	n.785T>G		non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000510756.1	A0A8I5KPP9
AP2A2	ENST00000693238.1 link	n.785T>G		non_coding_transcript_exon_variant	Exon 7 of 20			ENSP00000510648.1	A0A8I5KPP9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460676

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726676

show subpopulations

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.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Pathogenic

0.21

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

.;.;T;D

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;.;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

-0.22

MutationAssessor

Pathogenic

3.4

M;.;.;M

PrimateAI

Pathogenic

0.86

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over