chr12-57731596-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001122772.3(AGAP2):​c.2000G>T​(p.Gly667Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

AGAP2
NM_001122772.3 missense

Scores

1
1
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.51
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.13019091).
BS2
High AC in GnomAdExome4 at 11 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGAP2NM_001122772.3 linkuse as main transcriptc.2000G>T p.Gly667Val missense_variant 9/19 ENST00000547588.6 NP_001116244.1
AGAP2NM_014770.4 linkuse as main transcriptc.992G>T p.Gly331Val missense_variant 9/18 NP_055585.1
AGAP2XM_005268625.4 linkuse as main transcriptc.2000G>T p.Gly667Val missense_variant 9/18 XP_005268682.1
AGAP2XM_005268626.3 linkuse as main transcriptc.992G>T p.Gly331Val missense_variant 9/19 XP_005268683.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AGAP2ENST00000547588.6 linkuse as main transcriptc.2000G>T p.Gly667Val missense_variant 9/191 NM_001122772.3 ENSP00000449241 P3
AGAP2ENST00000257897.7 linkuse as main transcriptc.992G>T p.Gly331Val missense_variant 9/181 ENSP00000257897 A1Q99490-2
AGAP2ENST00000328568.9 linkuse as main transcriptc.1592G>T p.Gly531Val missense_variant 9/185 ENSP00000328160
AGAP2ENST00000549129.1 linkuse as main transcriptc.68G>T p.Gly23Val missense_variant 2/53 ENSP00000446683

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152118
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251484
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135916
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461892
Hom.:
0
Cov.:
33
AF XY:
0.00000413
AC XY:
3
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000662
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152118
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000165
AC:
2

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 GeneticsJan 04, 2024The c.2000G>T (p.G667V) alteration is located in exon 9 (coding exon 9) of the AGAP2 gene. This alteration results from a G to T substitution at nucleotide position 2000, causing the glycine (G) at amino acid position 667 to be replaced by a valine (V). 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
-0.19
T
BayesDel_noAF
Benign
-0.33
CADD
Pathogenic
26
DANN
Benign
0.70
DEOGEN2
Benign
0.016
.;.;T
Eigen
Benign
-0.0028
Eigen_PC
Benign
0.089
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Benign
0.50
T;T;T
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.13
T;T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Benign
-1.9
N;N;N
REVEL
Benign
0.14
Sift
Benign
0.41
T;T;T
Sift4G
Benign
0.21
T;T;T
Polyphen
0.036
B;P;.
Vest4
0.20
MutPred
0.29
.;Gain of MoRF binding (P = 0.0918);.;
MVP
0.36
MPC
1.5
ClinPred
0.37
T
GERP RS
4.9
gMVP
0.48

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs771238162; hg19: chr12-58125379; API