12-57738231-C-T

Variant names:

• chr12-57738231-C-T
• rs1228237357
• NM_001122772.3:c.16G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001122772.3(AGAP2):​c.16G>A​(p.Gly6Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000439 in 1,365,674 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: 32)
  • Exomes 𝑓: 0.0000044 (0 hom.)
• Consequence: AGAP2 NM_001122772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.315
• 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]

TSPAN31 (HGNC:10539): (tetraspanin 31) The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is thought to be involved in growth-related cellular processes. This gene is associated with tumorigenesis and osteosarcoma. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12270486).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGAP2	NM_001122772.3	c.16G>A	p.Gly6Ser	missense_variant	Exon 1 of 19	ENST00000547588.6	NP_001116244.1
AGAP2	XM_005268625.4	c.16G>A	p.Gly6Ser	missense_variant	Exon 1 of 18		XP_005268682.1
AGAP2	NM_014770.4	c.161-2804G>A		intron_variant	Intron 1 of 17		NP_055585.1
AGAP2	XM_005268626.3	c.161-2804G>A		intron_variant	Intron 1 of 18		XP_005268683.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGAP2	ENST00000547588.6	c.16G>A	p.Gly6Ser	missense_variant	Exon 1 of 19	1	NM_001122772.3	ENSP00000449241.1
AGAP2	ENST00000257897.7	c.161-2804G>A		intron_variant	Intron 1 of 17	1		ENSP00000257897.3
TSPAN31	ENST00000553221.5	n.189+30C>T		intron_variant	Intron 1 of 5	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000874 AC: 1 AN: 114362 AF XY: 0.0000158

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000241

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000439 AC: 6 AN: 1365674 Hom.: 0 Cov.: 32 AF XY: 0.00000297 AC XY: 2 AN XY: 673440

African (AFR) AF: 0.00 AC: 0 AN: 28712

American (AMR) AF: 0.00 AC: 0 AN: 34760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24352

East Asian (EAS) AF: 0.00 AC: 0 AN: 33516

South Asian (SAS) AF: 0.00 AC: 0 AN: 78564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5544

European-Non Finnish (NFE) AF: 0.00000467 AC: 5 AN: 1070020

Other (OTH) AF: 0.0000176 AC: 1 AN: 56918

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>A (p.G6S) alteration is located in exon 1 (coding exon 1) of the AGAP2 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the glycine (G) at amino acid position 6 to be replaced by a serine (S). 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	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	24
DANN	Uncertain	1.0
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.32
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.042
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.021	D
Polyphen		0.0030	B
Vest4		0.18
MutPred		0.38		Gain of glycosylation at G6 (P = 0.0307);
MVP		0.46
MPC		2.9
ClinPred		0.39	T
GERP RS		-1.2
PromoterAI		-0.00040	Neutral
gMVP		0.35
Mutation Taster		=97/3	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: rs1228237357; hg19: chr12-58132014;