chr12-57727170-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BS2

The NM_001122772.3(AGAP2):ā€‹c.3140T>Gā€‹(p.Leu1047Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000343 in 1,457,044 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

AGAP2
NM_001122772.3 missense

Scores

4
9
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.36
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 Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGAP2NM_001122772.3 linkuse as main transcriptc.3140T>G p.Leu1047Arg missense_variant 18/19 ENST00000547588.6 NP_001116244.1
AGAP2-AS1NR_027032.1 linkuse as main transcriptn.345A>C 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.3140T>G p.Leu1047Arg missense_variant 18/191 NM_001122772.3 ENSP00000449241 P3
AGAP2-AS1ENST00000542466.2 linkuse as main transcriptn.314A>C non_coding_transcript_exon_variant 2/21

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000423
AC:
1
AN:
236488
Hom.:
0
AF XY:
0.00000772
AC XY:
1
AN XY:
129502
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.000174
GnomAD4 exome
AF:
0.00000343
AC:
5
AN:
1457044
Hom.:
0
Cov.:
33
AF XY:
0.00000414
AC XY:
3
AN XY:
724604
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000827
AC:
1

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 24, 2023The c.3140T>G (p.L1047R) alteration is located in exon 18 (coding exon 18) of the AGAP2 gene. This alteration results from a T to G substitution at nucleotide position 3140, causing the leucine (L) at amino acid position 1047 to be replaced by an arginine (R). 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
Pathogenic
0.17
D
BayesDel_noAF
Uncertain
0.0
CADD
Uncertain
25
DANN
Uncertain
1.0
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.98
D;D
M_CAP
Benign
0.032
D
MetaRNN
Uncertain
0.43
T;T
MetaSVM
Benign
-0.28
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.64
T
PROVEAN
Pathogenic
-4.9
D;D
REVEL
Uncertain
0.40
Sift
Uncertain
0.0010
D;D
Sift4G
Pathogenic
0.0010
D;D
Polyphen
1.0
D;P
Vest4
0.46
MutPred
0.55
.;Gain of disorder (P = 0.0359);
MVP
0.76
MPC
3.1
ClinPred
0.99
D
GERP RS
5.0
gMVP
0.97

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: rs759363357; hg19: chr12-58120953; API