NM_001353921.2:c.*178_*181dupCACA

Variant names:

• chrX-63637846-C-CTGTG
• rs10542660
• NM_001353921.2:c.*178_*181dupCACA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001353921.2(ARHGEF9):​c.*178_*181dupCACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., 19 hem., cov: 12)
  • Exomes 𝑓: 0.0011 (0 hom. 7 hem.)
• Consequence: ARHGEF9 NM_001353921.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 1 publications found

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]

ARHGEF9 Gene-Disease associations (from GenCC):

• developmental and epileptic encephalopathy, 8

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, G2P
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353921.2. 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
	ARHGEF9	NM_001353921.2	MANE Select	c.*178_*181dupCACA		3_prime_UTR	Exon 10 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.*178_*181dupCACA		3_prime_UTR	Exon 10 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.*178_*181dupCACA		3_prime_UTR	Exon 11 of 11	NP_001355959.1	O43307-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARHGEF9	ENST00000671741.2	MANE Select	c.*178_*181dupCACA		3_prime_UTR	Exon 10 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.*178_*181dupCACA		3_prime_UTR	Exon 10 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.1375-2442_1375-2439dupCACA		intron	N/A	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes AF: 0.00146 AC: 142 AN: 97022 Hom.: 2 Cov.: 12

Gnomad AFR AF: 0.000466

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00127

Gnomad SAS AF: 0.00142

Gnomad FIN AF: 0.000866

Gnomad MID AF: 0.00966

Gnomad NFE AF: 0.00181

Gnomad OTH AF: 0.00233

GnomAD4 exome AF: 0.00106 AC: 225 AN: 213192 Hom.: 0 Cov.: 0 AF XY: 0.000110 AC XY: 7 AN XY: 63440

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

African (AFR) AF: 0.000150 AC: 1 AN: 6675

American (AMR) AF: 0.00291 AC: 24 AN: 8250

Ashkenazi Jewish (ASJ) AF: 0.000440 AC: 3 AN: 6824

East Asian (EAS) AF: 0.000810 AC: 14 AN: 17275

South Asian (SAS) AF: 0.000264 AC: 2 AN: 7586

European-Finnish (FIN) AF: 0.000675 AC: 10 AN: 14809

Middle Eastern (MID) AF: 0.00439 AC: 4 AN: 911

European-Non Finnish (NFE) AF: 0.00111 AC: 153 AN: 137540

Other (OTH) AF: 0.00105 AC: 14 AN: 13322

⚠️ 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 AF: 0.00146 AC: 142 AN: 97036 Hom.: 2 Cov.: 12 AF XY: 0.000799 AC XY: 19 AN XY: 23786

African (AFR) AF: 0.000465 AC: 12 AN: 25783

American (AMR) AF: 0.00308 AC: 27 AN: 8767

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2390

East Asian (EAS) AF: 0.00128 AC: 4 AN: 3131

South Asian (SAS) AF: 0.00144 AC: 3 AN: 2090

European-Finnish (FIN) AF: 0.000866 AC: 4 AN: 4618

Middle Eastern (MID) AF: 0.0108 AC: 2 AN: 186

European-Non Finnish (NFE) AF: 0.00181 AC: 87 AN: 48123

Other (OTH) AF: 0.00230 AC: 3 AN: 1305

Alfa AF: 0.00122 Hom.: 45

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10542660; hg19: chrX-62857726;