X-53247131-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_001111125.3(IQSEC2):c.2587C>T(p.Arg863Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 4.50

Publications

10 publications found

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]

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

IQSEC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant X-53247131-G-A is Pathogenic according to our data. Variant chrX-53247131-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 10862.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IQSEC2	NM_001111125.3	MANE Select	c.2587C>T	p.Arg863Trp	missense	Exon 8 of 15	NP_001104595.1
IQSEC2	NM_001441092.1		c.2587C>T	p.Arg863Trp	missense	Exon 8 of 14	NP_001428021.1
IQSEC2	NM_001410736.1		c.2587C>T	p.Arg863Trp	missense	Exon 8 of 14	NP_001397665.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IQSEC2	ENST00000642864.1	MANE Select	c.2587C>T	p.Arg863Trp	missense	Exon 8 of 15	ENSP00000495726.1
IQSEC2	ENST00000375365.2	TSL:1	c.1972C>T	p.Arg658Trp	missense	Exon 8 of 14	ENSP00000364514.2
IQSEC2	ENST00000706952.1		c.2746C>T	p.Arg916Trp	missense	Exon 8 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1095751

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

361221

African (AFR)

AF:

0.00

AC:

AN:

26364

American (AMR)

AF:

0.00

AC:

AN:

35047

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19345

East Asian (EAS)

AF:

0.00

AC:

AN:

30161

South Asian (SAS)

AF:

0.00

AC:

AN:

53630

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40350

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4034

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840817

Other (OTH)

AF:

0.00

AC:

AN:

46003

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Mar 21, 2025

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31490346, 32529990, 26733290, 27009485, 20473311, 26793055, 27665735, 24306141, 30328660, 27010919, 36902414, 27369185)

Feb 13, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intellectual disability, X-linked 1

Pathogenic:1

Jun 01, 2010

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Intellectual disability

Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.12

PhyloP100

4.5

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.9

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MutPred

0.69

Loss of catalytic residue at R863 (P = 0.2465)

MVP

0.97

MPC

2.3

ClinPred

1.0

GERP RS

3.6

Varity_R

0.98

gMVP

0.97

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over