rs1064795512

Variant names:

• chrX-53234646-G-GC
• rs1064795512
• NM_001111125.3:c.4039dupG

Your query was ambiguous. Multiple possible variants found:

• chrX-53234646-G-GC
• chrX-53234646-G-GCC

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001111125.3(IQSEC2):​c.4039dupG​(p.Ala1347GlyfsTer40) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A1347A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC2 NM_001111125.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.124
• Publications: 6 publications found

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]

IQSEC2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• intellectual disability, X-linked 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 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 21 pathogenic variants in the truncated region.
• PP5: Variant X-53234646-G-GC is Pathogenic according to our data. Variant chrX-53234646-G-GC is described in ClinVar as Pathogenic. ClinVar VariationId is 422032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.4039dupG	p.Ala1347GlyfsTer40	frameshift_variant	Exon 15 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4039dupG	p.Ala1347GlyfsTer40	frameshift_variant	Exon 15 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1024792 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 326776

African (AFR) AF: 0.00 AC: 0 AN: 24292

American (AMR) AF: 0.00 AC: 0 AN: 24442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16259

East Asian (EAS) AF: 0.00 AC: 0 AN: 26932

South Asian (SAS) AF: 0.00 AC: 0 AN: 44305

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3876

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 805421

Other (OTH) AF: 0.00 AC: 0 AN: 43109

GnomAD4 genome Cov.: 20

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 1 Pathogenic:1

Jun 23, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala1347Glyfs*40) in the IQSEC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 142 amino acid(s) of the IQSEC2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with epileptic encephalopathy, microcephaly and autism spectrum disorder (PMID: 27864847). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 422032). This variant disrupts a region of the IQSEC2 protein in which other variant(s) (p.Lys1480Argfs*17) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Mar 14, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 142 amino acids are replaced with 39 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27864847, 30206421) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.12
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1064795512; hg19: chrX-53263828;