chrX-63637846-CTGTGTG-C

Variant names:

• chrX-63637846-CTGTGTG-C
• rs10542660
• NM_001353921.2:c.*176_*181delCACACA

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001353921.2(ARHGEF9):​c.*176_*181delCACACA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 308,742 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 81 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., 53 hem., cov: 12)
  • Exomes 𝑓: 0.0023 (0 hom. 28 hem.)
• Consequence: ARHGEF9 NM_001353921.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64

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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.00226 (478/211726) while in subpopulation AFR AF= 0.0278 (177/6378). AF 95% confidence interval is 0.0244. There are 0 homozygotes in gnomad4_exome. There are 28 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 53 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARHGEF9	NM_001353921.2	c.*176_*181delCACACA		3_prime_UTR_variant	Exon 10 of 10	ENST00000671741.2	NP_001340850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARHGEF9	ENST00000671741	c.*176_*181delCACACA		3_prime_UTR_variant	Exon 10 of 10		NM_001353921.2	ENSP00000500715.1

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 215 AN: 97004 Hom.: 0 Cov.: 12 AF XY: 0.00215 AC XY: 51 AN XY: 23748

Gnomad AFR AF: 0.00641

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000799

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000318

Gnomad SAS AF: 0.00142

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00966

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.00233

GnomAD4 exome AF: 0.00226 AC: 478 AN: 211726 Hom.: 0 AF XY: 0.000448 AC XY: 28 AN XY: 62522

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00171

Gnomad4 ASJ exome AF: 0.00118

Gnomad4 EAS exome AF: 0.000755

Gnomad4 SAS exome AF: 0.00226

Gnomad4 FIN exome AF: 0.00122

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.00227 AC: 220 AN: 97016 Hom.: 0 Cov.: 12 AF XY: 0.00223 AC XY: 53 AN XY: 23770

Gnomad4 AFR AF: 0.00656

Gnomad4 AMR AF: 0.000798

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000319

Gnomad4 SAS AF: 0.00144

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000707

Gnomad4 OTH AF: 0.00307

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10542660; hg19: chrX-62857726;