14-23561355-G-A

Position:

• chr14-23561355-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003917.5(AP1G2):​c.1934C>T​(p.Pro645Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,436,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: AP1G2 NM_003917.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13438323).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AP1G2	NM_003917.5	c.1934C>T	p.Pro645Leu	missense_variant	19/22	ENST00000397120.8	NP_003908.1
AP1G2-AS1	NR_110555.1	n.259G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AP1G2	ENST00000397120.8	c.1934C>T	p.Pro645Leu	missense_variant	19/22	1	NM_003917.5	ENSP00000380309	P1
AP1G2-AS1	ENST00000555968.1	n.259G>A		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1436956 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 712282

Gnomad4 AFR exome AF: 0.0000918

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: 0.00

Gnomad4 NFE exome AF: 9.11e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 08, 2023

The c.1934C>T (p.P645L) alteration is located in exon 19 (coding exon 18) of the AP1G2 gene. This alteration results from a C to T substitution at nucleotide position 1934, causing the proline (P) at amino acid position 645 to be replaced by a leucine (L). 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	Benign	0.071
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.051	T;T;.
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.76	.;T;T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.049
Sift	Benign	0.042	D;D;T
Sift4G	Benign	0.11	T;T;.
Polyphen		0.0010	B;B;.
Vest4		0.096
MutPred		0.26		Loss of glycosylation at S646 (P = 0.0586);Loss of glycosylation at S646 (P = 0.0586);.;
MVP		0.28
MPC		0.12
ClinPred		0.15	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1884522699; hg19: chr14-24030564;