rs2281680

Variant names:

• chr14-23563861-C-T
• rs2281680
• NM_003917.5:c.1092-5G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003917.5(AP1G2):​c.1092-5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,612,872 control chromosomes in the GnomAD database, including 28,381 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.14 (1844 hom., cov: 32)
  • Exomes 𝑓: 0.19 (26537 hom.)
• Consequence: AP1G2 NM_003917.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004158
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566
• Publications: 21 publications found

Genes affected

AP1G2 (HGNC:556): (adaptor related protein complex 1 subunit gamma 2) Adaptins are important components of clathrin-coated vesicles transporting ligand-receptor complexes from the plasma membrane or from the trans-Golgi network to lysosomes. The adaptin family of proteins is composed of four classes of molecules named alpha, beta-, beta prime- and gamma- adaptins. Adaptins, together with medium and small subunits, form a heterotetrameric complex called an adaptor, whose role is to promote the formation of clathrin-coated pits and vesicles. The protein encoded by this gene is a gamma-adaptin protein and it belongs to the adaptor complexes large subunits family. This protein along with the complex is thought to function at some trafficking step in the complex pathways between the trans-Golgi network and the cell surface. [provided by RefSeq, Aug 2017]

AP1G2-AS1 (HGNC:55442): (AP1G2 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AP1G2	NM_003917.5	c.1092-5G>A		splice_region_variant, intron_variant	Intron 11 of 21	ENST00000397120.8	NP_003908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AP1G2	ENST00000397120.8	c.1092-5G>A		splice_region_variant, intron_variant	Intron 11 of 21	1	NM_003917.5	ENSP00000380309.3

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20795 AN: 152106 Hom.: 1835 Cov.: 32

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.297

Gnomad FIN AF: 0.0974

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.185

Gnomad OTH AF: 0.166

GnomAD2 exomes AF: 0.178 AC: 44014 AN: 247360 AF XY: 0.186

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.170

Gnomad EAS exome AF: 0.118

Gnomad FIN exome AF: 0.104

Gnomad NFE exome AF: 0.182

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.186 AC: 271706 AN: 1460646 Hom.: 26537 Cov.: 34 AF XY: 0.190 AC XY: 137898 AN XY: 726452

African (AFR) AF: 0.0282 AC: 943 AN: 33468

American (AMR) AF: 0.204 AC: 9126 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 4468 AN: 26076

East Asian (EAS) AF: 0.139 AC: 5513 AN: 39680

South Asian (SAS) AF: 0.297 AC: 25621 AN: 86182

European-Finnish (FIN) AF: 0.103 AC: 5468 AN: 53214

Middle Eastern (MID) AF: 0.194 AC: 1119 AN: 5764

European-Non Finnish (NFE) AF: 0.188 AC: 208790 AN: 1111272

Other (OTH) AF: 0.177 AC: 10658 AN: 60316

GnomAD4 genome AF: 0.137 AC: 20815 AN: 152226 Hom.: 1844 Cov.: 32 AF XY: 0.136 AC XY: 10111 AN XY: 74434

African (AFR) AF: 0.0339 AC: 1409 AN: 41550

American (AMR) AF: 0.169 AC: 2578 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 542 AN: 3470

East Asian (EAS) AF: 0.125 AC: 647 AN: 5172

South Asian (SAS) AF: 0.299 AC: 1444 AN: 4826

European-Finnish (FIN) AF: 0.0974 AC: 1033 AN: 10610

Middle Eastern (MID) AF: 0.170 AC: 50 AN: 294

European-Non Finnish (NFE) AF: 0.185 AC: 12566 AN: 67986

Other (OTH) AF: 0.171 AC: 362 AN: 2114

Alfa AF: 0.172 Hom.: 7097

Bravo AF: 0.136

Asia WGS AF: 0.228 AC: 792 AN: 3478

EpiCase AF: 0.187

EpiControl AF: 0.191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.4
DANN	Benign	0.88
PhyloP100		-0.57
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs2281680; hg19: chr14-24033070; COSMIC: COSV55338577; COSMIC: COSV55338577;