X-53234247-T-TTGGCC
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP5_Moderate
The NM_001111125.3(IQSEC2):c.4438_4439insGGCCA(p.Lys1480ArgfsTer17) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 16)
Consequence
IQSEC2
NM_001111125.3 frameshift
NM_001111125.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.13
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1606 codons.
PP5
Variant X-53234247-T-TTGGCC is Pathogenic according to our data. Variant chrX-53234247-T-TTGGCC is described in ClinVar as [Pathogenic]. Clinvar id is 471275.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IQSEC2 | NM_001111125.3 | c.4438_4439insGGCCA | p.Lys1480ArgfsTer17 | frameshift_variant | 15/15 | ENST00000642864.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IQSEC2 | ENST00000642864.1 | c.4438_4439insGGCCA | p.Lys1480ArgfsTer17 | frameshift_variant | 15/15 | NM_001111125.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 16
GnomAD3 genomes
Cov.:
16
GnomAD4 exome Cov.: 22
GnomAD4 exome
Cov.:
22
GnomAD4 genome Cov.: 16
GnomAD4 genome
Cov.:
16
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Intellectual disability, X-linked 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 31, 2017 | Family studies have indicated that this variant was not present in the parents of an individual with clinical features consistent with an IQSEC2-related condition, which suggests that it was de novo in that affected individual (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with IQSEC2-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change inserts 5 nucleotides in exon 15 of the IQSEC2 mRNA (c.4434_4438dupGGCCA), causing a frameshift at codon 1480 (p.Lys1480Argfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acids and extend the length of the IQSEC2 protein by 7 additional amino acids. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at