10-50008862-G-A

Position:

chr10-50008862-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000412531.7(AGAP6):c.737G>A(p.Arg246Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000394 in 152,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000060 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AGAP6
ENST00000412531.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

Variant links:

Genes affected

AGAP6 (HGNC:23466): (ArfGAP with GTPase domain, ankyrin repeat and PH domain 6) Predicted to enable GTPase activator activity and metal ion binding activity. Predicted to be involved in regulation of catalytic activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

AGAP6 links:

TIMM23B-AGAP6 (HGNC:45009): (TIMM23B-AGAP6 readthrough (NMD candidate)) This locus represents naturally-occurring readthrough transcription between the adjacent TIMM23B (translocase of inner mitochondrial membrane 23 homolog B) and AGAP6 (ArfGAP with GTPase domain, ankyrin repeat and PH domain 6) genes. Readthrough transcripts contain portions of the coding sequence for both genes and are predicted to be candidates for nonsense-mediated decay (NMD). [provided by RefSeq, Sep 2018]

TIMM23B-AGAP6 links:

AGAP6 (HGNC:):

AGAP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.016781956).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGAP6	NM_001077665.3 linkuse as main transcript	c.737G>A	p.Arg246Gln	missense_variant	8/8	ENST00000412531.7	NP_001071133.2	Q5VW22-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
AGAP6	ENST00000412531.7 linkuse as main transcript	c.737G>A	p.Arg246Gln	missense_variant	8/8	1	NM_001077665.3	ENSP00000500374.1	Q5VW22-2
TIMM23B-AGAP6	ENST00000651763.1 linkuse as main transcript	n.*952G>A		non_coding_transcript_exon_variant	17/18			ENSP00000502214.1
TIMM23B-AGAP6	ENST00000651763.1 linkuse as main transcript	n.*952G>A		3_prime_UTR_variant	17/18			ENSP00000502214.1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152010

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0197

AC:

AN:

4476

Hom.:

AF XY:

0.0177

AC XY:

AN XY:

2482

show subpopulations

Gnomad AFR exome

AF:

0.00350

Gnomad AMR exome

AF:

0.0590

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0311

Gnomad FIN exome

AF:

0.0435

Gnomad NFE exome

AF:

0.00181

Gnomad OTH exome

AF:

0.0125

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000595

AC:

AN:

1461858

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000585

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.0000360

AC:

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 submitter

clinical testing

Ambry Genetics

May 16, 2023

The c.737G>A (p.R246Q) alteration is located in exon 8 (coding exon 8) of the AGAP6 gene. This alteration results from a G to A substitution at nucleotide position 737, causing the arginine (R) at amino acid position 246 to be replaced by a glutamine (Q). 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

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.73

CADD

Benign

5.8

DANN

Benign

0.43

DEOGEN2

Benign

0.00043

.;T;.

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.030

LIST_S2

Benign

0.80

.;T;T

M_CAP

Benign

0.0015

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-1.9

.;N;.

MutationTaster

Benign

0.99

N;N

PrimateAI

Uncertain

0.53

REVEL

Benign

0.054

Sift4G

Benign

0.66

T;T;T

Vest4

0.12

MVP

0.014

ClinPred

0.026

GERP RS

-0.093

Varity_R

0.016

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over