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

Genomes: not found (cov: 15)
Exomes 𝑓: 0.0000024 ( 0 hom. 0 hem. )

Consequence

IQSEC2
NM_001111125.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 2.16
Variant links:
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 14 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-53234266-T-TG is Pathogenic according to our data. Variant chrX-53234266-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 975247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IQSEC2NM_001111125.3 linkuse as main transcriptc.4419_4420insC p.Ser1474GlnfsTer133 frameshift_variant 15/15 ENST00000642864.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IQSEC2ENST00000642864.1 linkuse as main transcriptc.4419_4420insC p.Ser1474GlnfsTer133 frameshift_variant 15/15 NM_001111125.3 P1Q5JU85-2

Frequencies

GnomAD3 genomes
Cov.:
15
GnomAD3 exomes
AF:
0.0000199
AC:
1
AN:
50130
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
8622
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000241
AC:
2
AN:
830420
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
235582
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000406
Gnomad4 NFE exome
AF:
0.00000147
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
15

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Intellectual disability, X-linked 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeJun 25, 2023This 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 providedclinical testingCentre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de LilleJan 01, 2019- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1569290954; hg19: chrX-53263448; API