chrX-53234266-T-TG
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001111125.3(IQSEC2):c.4419_4420insC(p.Ser1474GlnfsTer133) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000241 in 830,420 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1473P) has been classified as Likely benign.
Frequency
Consequence
NM_001111125.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IQSEC2 | NM_001111125.3 | c.4419_4420insC | p.Ser1474GlnfsTer133 | frameshift_variant | 15/15 | ENST00000642864.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IQSEC2 | ENST00000642864.1 | c.4419_4420insC | p.Ser1474GlnfsTer133 | frameshift_variant | 15/15 | NM_001111125.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 15
GnomAD3 exomes AF: 0.0000199 AC: 1AN: 50130Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 8622
GnomAD4 exome AF: 0.00000241 AC: 2AN: 830420Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 235582
GnomAD4 genome Cov.: 15
ClinVar
Submissions by phenotype
Intellectual disability, X-linked 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 25, 2023 | This frameshift has been observed in individual(s) with IQSEC2-related conditions (PMID: 30666632). In at least one individual the variant was observed to be de novo. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change results in a frameshift in the IQSEC2 gene (p.Ser1474Glnfs*133). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 15 amino acid(s) of the IQSEC2 protein and extend the protein by 117 additional amino acid residues. ClinVar contains an entry for this variant (Variation ID: 975247). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille | Jan 01, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at