rs781823638

Positions:

• chrX-63724576-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001353921.2(ARHGEF9):​c.166C>A​(p.Gln56Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000397 in 1,208,796 control chromosomes in the GnomAD database, including 1 homozygotes. There are 28 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000042 (1 hom. 28 hem.)
• Consequence: ARHGEF9 NM_001353921.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.43

Genes affected

ARHGEF9 (HGNC:14561): (Cdc42 guanine nucleotide exchange factor 9) The protein encoded by this gene is a Rho-like GTPase that switches between the active (GTP-bound) state and inactive (GDP-bound) state to regulate CDC42 and other genes. This brain-specific protein also acts as an adaptor protein for the recruitment of gephyrin and together these proteins facilitate receceptor recruitement in GABAnergic and glycinergic synapses. Defects in this gene are the cause of startle disease with epilepsy (STHEE), also known as hyperekplexia with epilepsy, as well as several other types of cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.067786574).
• BP6: Variant X-63724576-G-T is Benign according to our data. Variant chrX-63724576-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434308.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000181 (2/110656) while in subpopulation SAS AF= 0.000779 (2/2566). AF 95% confidence interval is 0.000138. There are 0 homozygotes in gnomad4. There are 0 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAdExome4 at 28 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARHGEF9	NM_001353921.2	c.166C>A	p.Gln56Lys	missense_variant	2/10	ENST00000671741.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARHGEF9	ENST00000671741.2	c.166C>A	p.Gln56Lys	missense_variant	2/10		NM_001353921.2	A1

Frequencies

GnomAD3 genomes AF: 0.0000181 AC: 2 AN: 110656 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32902

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000779

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000109 AC: 20 AN: 182944 Hom.: 0 AF XY: 0.000193 AC XY: 13 AN XY: 67484

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 SAS exome AF: 0.000997

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000419 AC: 46 AN: 1098140 Hom.: 1 Cov.: 31 AF XY: 0.0000770 AC XY: 28 AN XY: 363500

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000794

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.0000434

GnomAD4 genome AF: 0.0000181 AC: 2 AN: 110656 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 32902

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000779

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 27, 2016

- -

Developmental and epileptic encephalopathy, 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jun 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.50
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.062	T;T;.;T;T;T;T;T;.;T;.;T;T;T;T;T;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;.;D;.;.;.;D;.;D;.;.;.;D;D;D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.068	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.55	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	0.58	N;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.21	T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.
Sift4G	Benign	0.27	T;T;T;.;.;.;.;.;T;T;.;.;.;T;.;.;.;T;.;T
Polyphen		0.012	B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.26
MutPred		0.55		Gain of ubiquitination at Q49 (P = 0.0128);.;Gain of ubiquitination at Q49 (P = 0.0128);.;.;.;.;.;.;.;.;.;.;.;.;Gain of ubiquitination at Q49 (P = 0.0128);.;.;.;.;
MVP		0.76
MPC		1.3
ClinPred		0.14	T
GERP RS		5.5
Varity_R		0.60
gMVP		0.89

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: rs781823638; hg19: chrX-62944456; COSMIC: COSV53638703;