12-57727022-G-A

Variant names:

• chr12-57727022-G-A
• rs148957106
• NM_001122772.3:c.3288C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS2

The NM_001122772.3(AGAP2):​c.3288C>T​(p.His1096His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,609,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: AGAP2 NM_001122772.3 synonymous
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.63
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.067).
• BP6: Variant 12-57727022-G-A is Benign according to our data. Variant chr12-57727022-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3058699.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.63 with no splicing effect.
• BS2: High AC in GnomAd4 at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP2	NM_001122772.3	c.3288C>T	p.His1096His	synonymous_variant	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.3288C>T	p.His1096His	synonymous_variant	Exon 18 of 19	1	NM_001122772.3	ENSP00000449241.1

Frequencies

GnomAD3 genomes AF: 0.000657 AC: 100 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000150 AC: 36 AN: 240692 AF XY: 0.000122

Gnomad AFR exome AF: 0.00225

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000922

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000748 AC: 109 AN: 1456874 Hom.: 0 Cov.: 33 AF XY: 0.0000635 AC XY: 46 AN XY: 724660

African (AFR) AF: 0.00299 AC: 100 AN: 33396

American (AMR) AF: 0.0000450 AC: 2 AN: 44402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26016

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 85932

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110434

Other (OTH) AF: 0.0000665 AC: 4 AN: 60172

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000524 AC XY: 39 AN XY: 74474

African (AFR) AF: 0.00226 AC: 94 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000778

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AGAP2-related disorder Benign:1

Mar 29, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	18
DANN	Benign	0.97
PhyloP100		1.6

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: rs148957106; hg19: chr12-58120805;