chr12-57742040-G-A

Position:

• chr12-57742040-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000257897.7(AGAP2):​c.32C>T​(p.Ala11Val) variant causes a missense change. The variant allele was found at a frequency of 0.000605 in 1,614,088 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (11 hom.)
• Consequence: AGAP2 ENST00000257897.7 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 7.00

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009385824).
• BP6: Variant 12-57742040-G-A is Benign according to our data. Variant chr12-57742040-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3052503.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGAP2	NM_014770.4	c.32C>T	p.Ala11Val	missense_variant	1/18		NP_055585.1
AGAP2	XM_005268626.3	c.32C>T	p.Ala11Val	missense_variant	1/19		XP_005268683.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGAP2	ENST00000257897.7	c.32C>T	p.Ala11Val	missense_variant	1/18	1		ENSP00000257897	A1
TSPAN31	ENST00000547311.5	n.235+2070G>A		intron_variant, non_coding_transcript_variant		3
TSPAN31	ENST00000550528.5	n.105+2070G>A		intron_variant, non_coding_transcript_variant		3
TSPAN31	ENST00000553221.5	n.190-1200G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000819 AC: 206 AN: 251438 Hom.: 2 AF XY: 0.00124 AC XY: 168 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000308

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000640 AC: 936 AN: 1461842 Hom.: 11 Cov.: 33 AF XY: 0.000840 AC XY: 611 AN XY: 727236

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00587

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74424

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000315 Hom.: 0

Bravo AF: 0.000155

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000848 AC: 103

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

AGAP2-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 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_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	0.028
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.58	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0094	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.87	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.0050	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.073	B
Vest4		0.40
MVP		0.59
ClinPred		0.13	T
GERP RS		4.8

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: rs201928942; hg19: chr12-58135823;