X-63637846-CTGTGTGTGTGTGTGTGTGTGTGTG-CTGTGTGTGTGTGTGTGTGTGTGTGTG

Variant names:

• chrX-63637846-C-CTG
• rs10542660
• NM_001353921.2:c.*180_*181dupCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001353921.2(ARHGEF9):​c.*180_*181dupCA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.047 (120 hom., 806 hem., cov: 12)
  • Exomes 𝑓: 0.033 (5 hom. 159 hem.)
• Consequence: ARHGEF9 NM_001353921.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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), G2P, Ambry Genetics, Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant X-63637846-C-CTG is Benign according to our data. Variant chrX-63637846-C-CTG is described in ClinVar as Benign. ClinVar VariationId is 1249525.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0563 is higher than 0.05.

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.*180_*181dupCA		3_prime_UTR	Exon 10 of 10	NP_001340850.1	A0A5F9ZHY9
	ARHGEF9	NM_001353923.1		c.*180_*181dupCA		3_prime_UTR	Exon 10 of 10	NP_001340852.1	A0A1B0GWI5
	ARHGEF9	NM_001369030.1		c.*180_*181dupCA		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.*180_*181dupCA		3_prime_UTR	Exon 10 of 10	ENSP00000500715.1	A0A5F9ZHY9
	ARHGEF9	ENST00000253401.10	TSL:1	c.*180_*181dupCA		3_prime_UTR	Exon 10 of 10	ENSP00000253401.6	O43307-1
	ARHGEF9	ENST00000374878.5	TSL:1	c.1375-2440_1375-2439dupCA		intron	N/A	ENSP00000364012.2	B1AMR4

Frequencies

GnomAD3 genomes AF: 0.0472 AC: 4576 AN: 96937 Hom.: 122 Cov.: 12

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.0264

Gnomad AMR AF: 0.0480

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.0256

Gnomad FIN AF: 0.0411

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.0581

Gnomad OTH AF: 0.0685

GnomAD4 exome AF: 0.0333 AC: 6906 AN: 207305 Hom.: 5 Cov.: 0 AF XY: 0.00270 AC XY: 159 AN XY: 58931

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

African (AFR) AF: 0.0121 AC: 80 AN: 6629

American (AMR) AF: 0.0288 AC: 230 AN: 7998

Ashkenazi Jewish (ASJ) AF: 0.0705 AC: 457 AN: 6482

East Asian (EAS) AF: 0.0163 AC: 276 AN: 16983

South Asian (SAS) AF: 0.0172 AC: 125 AN: 7276

European-Finnish (FIN) AF: 0.0368 AC: 531 AN: 14439

Middle Eastern (MID) AF: 0.0761 AC: 66 AN: 867

European-Non Finnish (NFE) AF: 0.0347 AC: 4631 AN: 133644

Other (OTH) AF: 0.0393 AC: 510 AN: 12987

⚠️ 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: 0.0471 AC: 4569 AN: 96949 Hom.: 120 Cov.: 12 AF XY: 0.0340 AC XY: 806 AN XY: 23731

African (AFR) AF: 0.0218 AC: 561 AN: 25778

American (AMR) AF: 0.0480 AC: 420 AN: 8758

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 314 AN: 2386

East Asian (EAS) AF: 0.0320 AC: 100 AN: 3126

South Asian (SAS) AF: 0.0254 AC: 53 AN: 2089

European-Finnish (FIN) AF: 0.0411 AC: 189 AN: 4599

Middle Eastern (MID) AF: 0.177 AC: 33 AN: 186

European-Non Finnish (NFE) AF: 0.0581 AC: 2792 AN: 48081

Other (OTH) AF: 0.0691 AC: 90 AN: 1303

Alfa AF: 0.0170 Hom.: 45

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs10542660;

hg19: chrX-62857726;