12-57726635-T-C

Variant names:

• chr12-57726635-T-C
• rs936895004
• NM_001122772.3:c.3496A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001122772.3(AGAP2):​c.3496A>G​(p.Ser1166Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000477 in 1,047,240 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: AGAP2 NM_001122772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.172
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077885896).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP2	NM_001122772.3	c.3496A>G	p.Ser1166Gly	missense_variant	Exon 19 of 19	ENST00000547588.6	NP_001116244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP2	ENST00000547588.6	c.3496A>G	p.Ser1166Gly	missense_variant	Exon 19 of 19	1	NM_001122772.3	ENSP00000449241.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000477 AC: 5 AN: 1047240 Hom.: 0 Cov.: 32 AF XY: 0.00000606 AC XY: 3 AN XY: 494748

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21478

American (AMR) AF: 0.00 AC: 0 AN: 7172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12470

East Asian (EAS) AF: 0.00 AC: 0 AN: 22650

South Asian (SAS) AF: 0.00 AC: 0 AN: 20122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2908

European-Non Finnish (NFE) AF: 0.00000556 AC: 5 AN: 898612

Other (OTH) AF: 0.00 AC: 0 AN: 40974

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000020), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3496A>G (p.S1166G) alteration is located in exon 19 (coding exon 19) of the AGAP2 gene. This alteration results from a A to G substitution at nucleotide position 3496, causing the serine (S) at amino acid position 1166 to be replaced by a glycine (G). 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	-0.51
CADD	Benign	21
DANN	Benign	0.96
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.67	T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.078	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		0.17
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.24	N;N
REVEL	Benign	0.025
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.19	T;T
Polyphen		0.29	B;P
Vest4		0.066
MutPred		0.16		.;Loss of glycosylation at S1166 (P = 2e-04);
MVP		0.51
MPC		1.4
ClinPred		0.12	T
GERP RS		2.5
gMVP		0.25
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs936895004; hg19: chr12-58120418;