chr12-57727427-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001122772.3(AGAP2):​c.3013G>T​(p.Asp1005Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,326 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

AGAP2
NM_001122772.3 missense

Scores

8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.32
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.38375652).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGAP2NM_001122772.3 linkuse as main transcriptc.3013G>T p.Asp1005Tyr missense_variant 17/19 ENST00000547588.6 NP_001116244.1
AGAP2-AS1NR_027032.1 linkuse as main transcriptn.602C>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.3013G>T p.Asp1005Tyr missense_variant 17/191 NM_001122772.3 ENSP00000449241 P3
AGAP2-AS1ENST00000542466.2 linkuse as main transcriptn.571C>A non_coding_transcript_exon_variant 2/21

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461326
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726982
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 16, 2021The c.3013G>T (p.D1005Y) alteration is located in exon 17 (coding exon 17) of the AGAP2 gene. This alteration results from a G to T substitution at nucleotide position 3013, causing the aspartic acid (D) at amino acid position 1005 to be replaced by a tyrosine (Y). 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
BayesDel_addAF
Benign
-0.038
T
BayesDel_noAF
Benign
-0.29
CADD
Pathogenic
26
DANN
Uncertain
0.99
Eigen
Uncertain
0.43
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Benign
0.67
D
LIST_S2
Uncertain
0.91
D;D
M_CAP
Benign
0.031
D
MetaRNN
Benign
0.38
T;T
MetaSVM
Benign
-0.51
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Uncertain
-2.5
D;N
REVEL
Benign
0.16
Sift
Uncertain
0.027
D;D
Sift4G
Uncertain
0.030
D;D
Polyphen
0.29
B;P
Vest4
0.47
MutPred
0.59
.;Gain of loop (P = 0.002);
MVP
0.47
MPC
2.5
ClinPred
0.92
D
GERP RS
5.0
gMVP
0.83

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: chr12-58121210; API