rs2281680

Positions:

• chr14-23563861-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003917.5(AP1G2):​c.1092-5G>A variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00004158
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.566

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
AP1G2	NM_003917.5	c.1092-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000397120.8
AP1G2-AS1	NR_110555.1	n.778-866C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AP1G2	ENST00000397120.8	c.1092-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003917.5	P1
AP1G2-AS1	ENST00000555968.1	n.778-866C>T		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.178 AC: 44014 AN: 247360 Hom.: 4474 AF XY: 0.186 AC XY: 24948 AN XY: 133968

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 SAS exome AF: 0.297

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

Gnomad4 AFR exome AF: 0.0282

Gnomad4 AMR exome AF: 0.204

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.139

Gnomad4 SAS exome AF: 0.297

Gnomad4 FIN exome AF: 0.103

Gnomad4 NFE exome AF: 0.188

Gnomad4 OTH exome AF: 0.177

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

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.169

Gnomad4 ASJ AF: 0.156

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.299

Gnomad4 FIN AF: 0.0974

Gnomad4 NFE AF: 0.185

Gnomad4 OTH AF: 0.171

Alfa AF: 0.182 Hom.: 5316

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
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2

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

Publications

LitVar

Other links and lift over

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