X-53234266-T-TG

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.16

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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 4 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_single_submitter, 1 stars.

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: 1 AN: 50130 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 8622

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

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

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: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1569290954; hg19: chrX-53263448;