17-38466300-C-G

Variant names:

• chr17-38466300-C-G
• rs1385611329
• NM_001199417.2:c.617C>G

Variant summary

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

The NM_001199417.2(ARHGAP23):​c.617C>G​(p.Thr206Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,395,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T206I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ARHGAP23 NM_001199417.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.89
• Publications: 0 publications found

Genes affected

ARHGAP23 (HGNC:29293): (Rho GTPase activating protein 23) The RHO (see ARHA; MIM 165390) family of small GTPases are involved in signal transduction through transmembrane receptors, and they are inactive in the GDP-bound form and active in the GTP-bound form. GTPase-activating proteins, such as ARHGAP23, inactivate RHO family proteins by stimulating their hydrolysis of GTP (Katoh and Katoh, 2004 [PubMed 15254754]).[supplied by OMIM, Mar 2008]

ENSG00000276170 (HGNC:):

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=0.07200706).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199417.2. 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
	ARHGAP23	NM_001199417.2	MANE Select	c.617C>G	p.Thr206Ser	missense	Exon 7 of 24	NP_001186346.1	Q9P227-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGAP23	ENST00000622683.5	TSL:5 MANE Select	c.617C>G	p.Thr206Ser	missense	Exon 7 of 24	ENSP00000481862.1	Q9P227-1
	ARHGAP23	ENST00000616767.2	TSL:3	c.959C>G	p.Thr320Ser	missense	Exon 7 of 24	ENSP00000516485.1	A0A9L9PXS4
	ARHGAP23	ENST00000633445.2	TSL:3	c.563C>G	p.Thr188Ser	missense	Exon 7 of 24	ENSP00000516484.1	A0A9L9PXQ2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000669 AC: 1 AN: 149504 AF XY: 0.0000125

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1395004 Hom.: 0 Cov.: 41 AF XY: 0.00000291 AC XY: 2 AN XY: 688254

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35734

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45148

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078856

Other (OTH) AF: 0.00 AC: 0 AN: 57964

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	17
DANN	Benign	0.90
DEOGEN2	Benign	0.00057	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.9
PrimateAI	Uncertain	0.65	T
Sift4G	Benign	0.31	T
Polyphen		0.0050	B
Vest4		0.092
MutPred		0.15		Loss of glycosylation at T206 (P = 0.012)
MVP		0.23
ClinPred		0.089	T
GERP RS		3.0
Varity_R		0.11
gMVP		0.21
Mutation Taster		=99/1	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: rs1385611329; hg19: chr17-36622541;