12-57727161-G-T

Variant names:

• chr12-57727161-G-T
• rs755112486
• NM_001122772.3:c.3149C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001122772.3(AGAP2):​c.3149C>A​(p.Ser1050*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,455,600 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. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AGAP2 NM_001122772.3 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.38
• Publications: 0 publications found

Genes affected

AGAP2 (HGNC:16921): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 2) The protein encoded by this gene belongs to the centaurin gamma-like family. It mediates anti-apoptotic effects of nerve growth factor by activating nuclear phosphoinositide 3-kinase. It is overexpressed in cancer cells, and promotes cancer cell invasion. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

AGAP2-AS1 (HGNC:48633): (AGAP2 antisense RNA 1) Biomarker of lung non-small cell carcinoma; malignant astrocytoma; and stomach cancer. [provided by Alliance of Genome Resources, Apr 2022]

OS9 (HGNC:16994): (OS9 endoplasmic reticulum lectin) This gene encodes a protein that is highly expressed in osteosarcomas. This protein binds to the hypoxia-inducible factor 1 (HIF-1), a key regulator of the hypoxic response and angiogenesis, and promotes the degradation of one of its subunits. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP2	NM_001122772.3	c.3149C>A	p.Ser1050*	stop_gained	Exon 18 of 19	ENST00000547588.6	NP_001116244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP2	ENST00000547588.6	c.3149C>A	p.Ser1050*	stop_gained	Exon 18 of 19	1	NM_001122772.3	ENSP00000449241.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1455600 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723756

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 43696

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25872

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 85446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110156

Other (OTH) AF: 0.0000166 AC: 1 AN: 60126

GnomAD4 genome Cov.: 33

Alfa AF: 0.000811 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.37
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.099	N
PhyloP100		1.4
Vest4		0.71
GERP RS		5.0
Mutation Taster		=13/187	disease causing (fs/PTC)

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

Other links and lift over

dbSNP: rs755112486; hg19: chr12-58120944;