chr10-50008030-C-G

Variant names:

• chr10-50008030-C-G
• rs782544196
• NM_001077665.3:c.539C>G

Variant summary

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

The NM_001077665.3(AGAP6):​c.539C>G​(p.Ala180Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,764 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: AGAP6 NM_001077665.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.852
• Publications: 0 publications found

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]

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]

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=0.23303077).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001077665.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGAP6	NM_001077665.3	MANE Select	c.539C>G	p.Ala180Gly	missense	Exon 7 of 8	NP_001071133.2	Q5VW22-2
	TIMM23B-AGAP6	NR_158654.1		n.1044C>G		non_coding_transcript_exon	Exon 12 of 13
	TIMM23B-AGAP6	NR_158656.1		n.1103C>G		non_coding_transcript_exon	Exon 13 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGAP6	ENST00000412531.7	TSL:1 MANE Select	c.539C>G	p.Ala180Gly	missense	Exon 7 of 8	ENSP00000500374.1	Q5VW22-2
	AGAP6	ENST00000374056.10	TSL:1	c.470C>G	p.Ala157Gly	missense	Exon 6 of 7	ENSP00000363168.6	Q5VW22-1
	AGAP6	ENST00000311652.11	TSL:1	c.539C>G	p.Ala180Gly	missense	Exon 7 of 8	ENSP00000309985.8	A0A087WSV4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247736 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000137 AC: 2 AN: 1459592 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726110

African (AFR) AF: 0.00 AC: 0 AN: 33406

American (AMR) AF: 0.0000447 AC: 2 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111806

Other (OTH) AF: 0.00 AC: 0 AN: 60196

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152172 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 74344

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.0041
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.85
PrimateAI	Uncertain	0.67	T
REVEL	Benign	0.12
Sift4G	Uncertain	0.011	D
Vest4		0.20
MVP		0.17
ClinPred		0.35	T
GERP RS		1.7
Varity_R		0.14
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs782544196; hg19: chr10-51767790;