12-57729733-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001122772.3(AGAP2):c.2463T>C(p.Ser821=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000141 in 1,613,474 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (3 hom., cov: 31)
  • Exomes 𝑓: 0.000080 (1 hom.)
• Consequence: AGAP2 NM_001122772.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.12

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]

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 12-57729733-A-G is Benign according to our data. Variant chr12-57729733-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3058107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.12 with no splicing effect.
• BS2: High AC in GnomAd at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGAP2	NM_001122772.3	c.2463T>C	p.Ser821=	synonymous_variant	13/19	ENST00000547588.6
AGAP2	NM_014770.4	c.1455T>C	p.Ser485=	synonymous_variant	13/18
AGAP2	XM_005268625.4	c.2463T>C	p.Ser821=	synonymous_variant	13/18
AGAP2	XM_005268626.3	c.1455T>C	p.Ser485=	synonymous_variant	13/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGAP2	ENST00000547588.6	c.2463T>C	p.Ser821=	synonymous_variant	13/19	1	NM_001122772.3	P3
AGAP2	ENST00000257897.7	c.1455T>C	p.Ser485=	synonymous_variant	13/18	1		A1
AGAP2	ENST00000328568.9	c.2055T>C	p.Ser685=	synonymous_variant	13/18	5

Frequencies

GnomAD3 genomes AF: 0.000678 AC: 103 AN: 152014 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000962

GnomAD3 exomes AF: 0.000187 AC: 47 AN: 250828 Hom.: 0 AF XY: 0.000170 AC XY: 23 AN XY: 135586

Gnomad AFR exome AF: 0.00247

Gnomad AMR exome AF: 0.000203

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: 0.00

GnomAD4 exome AF: 0.0000801 AC: 117 AN: 1461342 Hom.: 1 Cov.: 30 AF XY: 0.0000688 AC XY: 50 AN XY: 726992

Gnomad4 AFR exome AF: 0.00269

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.000723 AC: 110 AN: 152132 Hom.: 3 Cov.: 31 AF XY: 0.000834 AC XY: 62 AN XY: 74374

Gnomad4 AFR AF: 0.00248

Gnomad4 AMR AF: 0.000327

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: 0.000952

Alfa AF: 0.000483 Hom.: 0

Bravo AF: 0.000820

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AGAP2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
Cadd	Benign	8.1
Dann	Benign	0.84

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

Other links and lift over

dbSNP: rs149262637; hg19: chr12-58123516;