chr12-57727489-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001122772.3(AGAP2):​c.2951G>T​(p.Arg984Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 33)

Consequence

AGAP2
NM_001122772.3 missense

Scores

8
7
1

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 7.91
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.911

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGAP2NM_001122772.3 linkuse as main transcriptc.2951G>T p.Arg984Leu missense_variant 17/19 ENST00000547588.6 NP_001116244.1
AGAP2-AS1NR_027032.1 linkuse as main transcriptn.664C>A non_coding_transcript_exon_variant 2/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGAP2ENST00000547588.6 linkuse as main transcriptc.2951G>T p.Arg984Leu missense_variant 17/191 NM_001122772.3 ENSP00000449241 P3
AGAP2-AS1ENST00000542466.2 linkuse as main transcriptn.633C>A non_coding_transcript_exon_variant 2/21

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

AGAP2-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesApr 29, 2024The AGAP2 c.2951G>T variant is predicted to result in the amino acid substitution p.Arg984Leu. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
32
DANN
Uncertain
1.0
Eigen
Pathogenic
0.91
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.82
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.91
D;D
MetaSVM
Uncertain
0.0021
D
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Pathogenic
-6.6
D;D
REVEL
Uncertain
0.62
Sift
Uncertain
0.0010
D;D
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.75
.;Loss of loop (P = 0.0022);
MVP
0.84
MPC
2.8
ClinPred
1.0
D
GERP RS
5.0
gMVP
0.98

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-58121272; API