Genetic Variant NM_012305.4:c.979G>C (chr11-986801-G-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_012305.4(AP2A2):c.979G>C(p.Val327Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,896 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AP2A2
NM_012305.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.81

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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, 0.749

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2A2	NM_012305.4 link	c.979G>C	p.Val327Leu	missense_variant	Exon 9 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.979G>C	p.Val327Leu	missense_variant	Exon 9 of 22	1	NM_012305.4	ENSP00000413234.3	O94973-1
AP2A2	ENST00000332231.9 link	c.982G>C	p.Val328Leu	missense_variant	Exon 9 of 22	1		ENSP00000327694.5	O94973-2
AP2A2	ENST00000528815.5 link	n.982G>C		non_coding_transcript_exon_variant	Exon 9 of 21	2		ENSP00000431630.1	O94973-3
AP2A2	ENST00000687792.1 link	n.979G>C		non_coding_transcript_exon_variant	Exon 9 of 21			ENSP00000508951.1	A0A8I5KPP9
AP2A2	ENST00000687890.1 link	n.979G>C		non_coding_transcript_exon_variant	Exon 9 of 21			ENSP00000510756.1	A0A8I5KPP9
AP2A2	ENST00000693238.1 link	n.979G>C		non_coding_transcript_exon_variant	Exon 9 of 20			ENSP00000510648.1	A0A8I5KPP9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247516

Hom.:

AF XY:

0.00000743

AC XY:

AN XY:

134518

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:

0.0000329

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460896

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726678

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

DANN

Uncertain

0.97

DEOGEN2

Benign

0.34

.;T

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Benign

0.028

MetaRNN

Pathogenic

0.75

D;D

MetaSVM

Benign

-0.85

MutationAssessor

Uncertain

2.3

.;M

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.1

N;N

REVEL

Benign

0.29

Sift

Benign

0.063

T;T

Sift4G

Benign

0.30

T;T

Polyphen

0.99

D;D

Vest4

0.66

MutPred

0.65

.;Gain of relative solvent accessibility (P = 0.1259);

MVP

0.50

MPC

0.79

ClinPred

0.54

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over