rs374688346

Variant names:

• chr11-985531-C-G
• rs374688346
• NM_012305.4:c.911C>G

Your query was ambiguous. Multiple possible variants found:

• chr11-985531-C-G
• chr11-985531-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_012305.4(AP2A2):​c.911C>G​(p.Ala304Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,682 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: 0.0000014 (0 hom.)
• Consequence: AP2A2 NM_012305.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP2A2	NM_012305.4	c.911C>G	p.Ala304Gly	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.911C>G	p.Ala304Gly	missense_variant	Exon 8 of 22	1	NM_012305.4	ENSP00000413234.3
AP2A2	ENST00000332231.9	c.914C>G	p.Ala305Gly	missense_variant	Exon 8 of 22	1		ENSP00000327694.5
AP2A2	ENST00000528815.5	n.914C>G		non_coding_transcript_exon_variant	Exon 8 of 21	2		ENSP00000431630.1
AP2A2	ENST00000687792.1	n.911C>G		non_coding_transcript_exon_variant	Exon 8 of 21			ENSP00000508951.1
AP2A2	ENST00000687890.1	n.911C>G		non_coding_transcript_exon_variant	Exon 8 of 21			ENSP00000510756.1
AP2A2	ENST00000693238.1	n.911C>G		non_coding_transcript_exon_variant	Exon 8 of 20			ENSP00000510648.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461682 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727124

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	.;T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.3	.;.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.74
MutPred		0.53		.;Loss of stability (P = 0.063);Loss of stability (P = 0.063);
MVP		0.61
MPC		1.8
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.61
gMVP		0.35

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

Other links and lift over

dbSNP: rs374688346; hg19: chr11-985531; COSMIC: COSV59962076; COSMIC: COSV59962076;