chr12-57727716-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001122772.3(AGAP2):​c.2822A>T​(p.Lys941Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,168 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

AGAP2
NM_001122772.3 missense

Scores

8
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.28
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AGAP2NM_001122772.3 linkuse as main transcriptc.2822A>T p.Lys941Met missense_variant 16/19 ENST00000547588.6 NP_001116244.1
AGAP2-AS1NR_027032.1 linkuse as main transcriptn.891T>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.2822A>T p.Lys941Met missense_variant 16/191 NM_001122772.3 ENSP00000449241 P3
AGAP2-AS1ENST00000542466.2 linkuse as main transcriptn.860T>A non_coding_transcript_exon_variant 2/21

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000415
AC:
1
AN:
240744
Hom.:
0
AF XY:
0.00000768
AC XY:
1
AN XY:
130124
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:
0.000171
GnomAD4 exome
AF:
6.89e-7
AC:
1
AN:
1452168
Hom.:
0
Cov.:
33
AF XY:
0.00000139
AC XY:
1
AN XY:
721540
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:
9.04e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000113

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 GeneticsApr 25, 2023The c.2822A>T (p.K941M) alteration is located in exon 16 (coding exon 16) of the AGAP2 gene. This alteration results from a A to T substitution at nucleotide position 2822, causing the lysine (K) at amino acid position 941 to be replaced by a methionine (M). 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
Uncertain
0.096
D
BayesDel_noAF
Benign
-0.10
CADD
Pathogenic
26
DANN
Uncertain
1.0
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Benign
0.71
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Benign
0.024
T
MetaRNN
Uncertain
0.49
T;T
MetaSVM
Benign
-0.73
T
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Benign
0.26
Sift
Benign
0.037
D;D
Sift4G
Benign
0.068
T;D
Polyphen
1.0
D;D
Vest4
0.49
MutPred
0.60
.;Gain of loop (P = 0.0013);
MVP
0.67
MPC
2.8
ClinPred
0.95
D
GERP RS
4.5
gMVP
0.92

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: rs1347314682; hg19: chr12-58121499; API