NM_001111125.3:c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT

Variant names:

• chrX-53320973-GCTGGCCCTCCAGCTCCTCGATGCGCCGCCGCTGGGTTTCCAGCAGCTGCTGCTGGCTCTCGATGATGTTGTTCAGCTCCAGCAGGTACTCCACGGC-AT
• rs1556880284
• NM_001111125.3:c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_001111125.3(IQSEC2):​c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT​(p.Ala19IlefsTer32) variant causes a frameshift, synonymous change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A19A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: IQSEC2 NM_001111125.3 frameshift, synonymous
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.96
• Publications: 0 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 10 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 191 pathogenic variants in the truncated region.
• PP5: Variant X-53320973-GCTGGCCCTCCAGCTCCTCGATGCGCCGCCGCTGGGTTTCCAGCAGCTGCTGCTGGCTCTCGATGATGTTGTTCAGCTCCAGCAGGTACTCCACGGC-AT is Pathogenic according to our data. Variant chrX-53320973-GCTGGCCCTCCAGCTCCTCGATGCGCCGCCGCTGGGTTTCCAGCAGCTGCTGCTGGCTCTCGATGATGTTGTTCAGCTCCAGCAGGTACTCCACGGC-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 545445.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT	p.Ala19IlefsTer32	frameshift_variant, synonymous_variant	Exon 1 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.55_151delGCCGTGGAGTACCTGCTGGAGCTGAACAACATCATCGAGAGCCAGCAGCAGCTGCTGGAAACCCAGCGGCGGCGCATCGAGGAGCTGGAGGGCCAGCinsAT	p.Ala19IlefsTer32	frameshift_variant, synonymous_variant	Exon 1 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 1 Pathogenic:1

Feb 15, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.0

Splicing

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

Other links and lift over

dbSNP: rs1556880284; hg19: chrX-53350171;