rs1057520858
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001111125.3(IQSEC2):c.2776C>T(p.Arg926Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
IQSEC2
NM_001111125.3 stop_gained
NM_001111125.3 stop_gained
Scores
2
2
1
Clinical Significance
Conservation
PhyloP100: 4.48
Genes affected
IQSEC2 (HGNC:29059): (IQ motif and Sec7 domain ArfGEF 2) This gene encodes a guanine nucleotide exchange factor for the ARF family of small GTP-binding proteins. The encoded protein is a component of the postsynaptic density at excitatory synapses, and may play a critical role in cytoskeletal and synaptic organization through the activation of selected ARF substrates including ARF1 and ARF6. Mutations in this gene have been implicated in nonsyndromic X-linked cognitive disability. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-53243445-G-A is Pathogenic according to our data. Variant chrX-53243445-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 380487.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53243445-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IQSEC2 | NM_001111125.3 | c.2776C>T | p.Arg926Ter | stop_gained | 9/15 | ENST00000642864.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IQSEC2 | ENST00000642864.1 | c.2776C>T | p.Arg926Ter | stop_gained | 9/15 | NM_001111125.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 23
GnomAD3 genomes
?
Cov.:
23
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1063949Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 345501
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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0
AN:
1063949
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30
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0
AN XY:
345501
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 23
GnomAD4 genome
?
Cov.:
23
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Intellectual disability, X-linked 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 04, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 22, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 380487). This premature translational stop signal has been observed in individual(s) with Rett-like phenotype (PMID: 27062609, 31512412). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg926*) in the IQSEC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQSEC2 are known to be pathogenic (PMID: 21686261, 26793055, 27665735). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 01, 2023 | Identified in females with with developmental delay and autistic features referred for genetic testing at GeneDx and in published literature (PMID: 27062609); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30328660, 30206421, 31512412, 27062609) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A
Vest4
0.54, 0.50
GERP RS
Splicing
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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