Variant 11-926026-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_012305.4(AP2A2):c.5C>G(p.Pro2Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000239 in 1,257,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000024 ( 0 hom. )

Consequence

AP2A2
NM_012305.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.78

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:

AP2A2 (HGNC:):

AP2A2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013087273).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP2A2	NM_012305.4 linkuse as main transcript	c.5C>G	p.Pro2Arg	missense_variant	1/22	ENST00000448903.7	NP_036437.1	O94973-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AP2A2	ENST00000448903.7 linkuse as main transcript	c.5C>G	p.Pro2Arg	missense_variant	1/22	1	NM_012305.4	ENSP00000413234.3	O94973-1
AP2A2	ENST00000332231.9 linkuse as main transcript	c.5C>G	p.Pro2Arg	missense_variant	1/22	1		ENSP00000327694.5	O94973-2
AP2A2	ENST00000528815.5 linkuse as main transcript	n.5C>G		non_coding_transcript_exon_variant	1/21	2		ENSP00000431630.1	O94973-3
AP2A2	ENST00000687792.1 linkuse as main transcript	n.5C>G		non_coding_transcript_exon_variant	1/21			ENSP00000508951.1	A0A8I5KPP9
AP2A2	ENST00000687890.1 linkuse as main transcript	n.5C>G		non_coding_transcript_exon_variant	1/21			ENSP00000510756.1	A0A8I5KPP9
AP2A2	ENST00000693238.1 linkuse as main transcript	n.5C>G		non_coding_transcript_exon_variant	1/20			ENSP00000510648.1	A0A8I5KPP9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000304

AC:

AN:

98752

Hom.:

AF XY:

0.0000351

AC XY:

AN XY:

56976

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000204

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000239

AC:

AN:

1257820

Hom.:

Cov.:

AF XY:

0.00000323

AC XY:

AN XY:

620128

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:

0.0000679

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000892

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2021

The c.5C>G (p.P2R) alteration is located in exon 1 (coding exon 1) of the AP2A2 gene. This alteration results from a C to G substitution at nucleotide position 5, causing the proline (P) at amino acid position 2 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

0.86

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

.;T;T

Eigen

Benign

-0.068

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.97

D;D;D

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.5

L;.;L

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-4.7

D;D;D

REVEL

Benign

0.22

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.31

MutPred

0.47

Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);Gain of MoRF binding (P = 0);

MVP

0.65

MPC

1.9

ClinPred

0.93

GERP RS

1.6

Varity_R

0.74

gMVP

0.53

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over