X-63637846-C-CTGTGTGTGTGTGTGTG

Variant names:

• chrX-63637846-C-CTGTGTGTGTGTGTGTG
• rs10542660
• NM_001353921.2:c.*166_*181dupCACACACACACACACA

Variant summary

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

The NM_001353921.2(ARHGEF9):​c.*166_*181dupCACACACACACACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 12)
  • Exomes 𝑓: 0.0000094 (0 hom. 0 hem.)
• Consequence: ARHGEF9 NM_001353921.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.87
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

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.*166_*181dupCACACACACACACACA		3_prime_UTR	Exon 10 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.*166_*181dupCACACACACACACACA		3_prime_UTR	Exon 10 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.*166_*181dupCACACACACACACACA		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.*166_*181dupCACACACACACACACA		3_prime_UTR	Exon 10 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.*166_*181dupCACACACACACACACA		3_prime_UTR	Exon 10 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.1375-2454_1375-2439dupCACACACACACACACA		intron	N/A	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes Cov.: 12

GnomAD4 exome AF: 0.00000937 AC: 2 AN: 213484 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 63654

⚠️ 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: 6675

American (AMR) AF: 0.00 AC: 0 AN: 8273

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6829

East Asian (EAS) AF: 0.0000578 AC: 1 AN: 17305

South Asian (SAS) AF: 0.00 AC: 0 AN: 7595

European-Finnish (FIN) AF: 0.0000674 AC: 1 AN: 14833

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 917

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 137718

Other (OTH) AF: 0.00 AC: 0 AN: 13339

⚠️ 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.: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9

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;