rs781823638
Positions:
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
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
NM_001353921.2 missense
Scores
1
2
13
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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: 2AN: 110656Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 32902
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GnomAD3 exomes AF: 0.000109 AC: 20AN: 182944Hom.: 0 AF XY: 0.000193 AC XY: 13AN XY: 67484
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GnomAD4 exome AF: 0.0000419 AC: 46AN: 1098140Hom.: 1 Cov.: 31 AF XY: 0.0000770 AC XY: 28AN XY: 363500
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GnomAD4 genome ? AF: 0.0000181 AC: 2AN: 110656Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 32902
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;T;T;T;T;T;.;T;.;T;T;T;T;T;.;.;.;.
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;.;D;.;.;.;D;.;D;.;.;.;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D
PROVEAN
Benign
N;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.
REVEL
Benign
Sift
Benign
T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.
Sift4G
Benign
T;T;T;.;.;.;.;.;T;T;.;.;.;T;.;.;.;T;.;T
Polyphen
B;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4
MutPred
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
MPC
ClinPred
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at