NM_001111125.3:c.3729_3737delCCACCACCA

Variant names:

• chrX-53234948-ATGGTGGTGG-A
• rs782189881
• NM_001111125.3:c.3729_3737delCCACCACCA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP3 BP6

The NM_001111125.3(IQSEC2):​c.3729_3737delCCACCACCA​(p.His1244_His1246del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000285 in 1,051,404 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000029 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 7.26
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP3: Nonframeshift variant in repetitive region in NM_001111125.3
• BP6: Variant X-53234948-ATGGTGGTGG-A is Benign according to our data. Variant chrX-53234948-ATGGTGGTGG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 420371.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	NM_001111125.3	MANE Select	c.3729_3737delCCACCACCA	p.His1244_His1246del	disruptive_inframe_deletion	Exon 15 of 15	NP_001104595.1
	IQSEC2	NM_001410736.1		c.*214_*222delCCACCACCA		3_prime_UTR	Exon 14 of 14	NP_001397665.1
	IQSEC2	NM_001441093.1		c.*214_*222delCCACCACCA		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.3729_3737delCCACCACCA	p.His1244_His1246del	disruptive_inframe_deletion	Exon 15 of 15	ENSP00000495726.1
	IQSEC2	ENST00000375365.2	TSL:1	c.*214_*222delCCACCACCA		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2
	IQSEC2	ENST00000706952.1		c.3888_3896delCCACCACCA	p.His1297_His1299del	disruptive_inframe_deletion	Exon 15 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.00000950 AC: 1 AN: 105302 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000534

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000285 AC: 3 AN: 1051404 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 343286

African (AFR) AF: 0.00 AC: 0 AN: 24850

American (AMR) AF: 0.0000359 AC: 1 AN: 27882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18608

East Asian (EAS) AF: 0.00 AC: 0 AN: 27094

South Asian (SAS) AF: 0.00 AC: 0 AN: 49749

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37512

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3881

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 817553

Other (OTH) AF: 0.0000226 AC: 1 AN: 44275

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3729_3737delCCACCACCA (p.H1245_H1247del) alteration is located in exon 15 (coding exon 15) of the IQSEC2 gene. This alteration consists of an in-frame deletion of 9 nucleotides between nucleotide positions c.3729 and c.3737, resulting in the deletion of 3 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Intellectual disability, X-linked 1 Benign:1

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Oct 25, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.3
Mutation Taster		=181/19	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs782189881; hg19: chrX-53264130;