rs1556865202

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001111125.3(IQSEC2):c.746G>C(p.Gly249Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,359 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 1 hem. )

Failed GnomAD Quality Control

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.31

Publications

0 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22106105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 link	c.746G>C	p.Gly249Ala	missense_variant	Exon 3 of 15	ENST00000642864.1	NP_001104595.1	Q5JU85-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1 link	c.746G>C	p.Gly249Ala	missense_variant	Exon 3 of 15		NM_001111125.3	ENSP00000495726.1		Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112359

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000323

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000933

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000189

AC:

AN:

1056574

Hom.:

Cov.:

AF XY:

0.00000297

AC XY:

AN XY:

336518

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

25383

American (AMR)

AF:

0.0000326

AC:

AN:

30690

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16798

East Asian (EAS)

AF:

0.00

AC:

AN:

29558

South Asian (SAS)

AF:

0.00

AC:

AN:

47280

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3341

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

820722

Other (OTH)

AF:

0.0000226

AC:

AN:

44216

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112359

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

34529

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30918

American (AMR)

AF:

0.0000933

AC:

AN:

10718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2727

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6211

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53127

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 06, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.746G>C (p.G249A) alteration is located in exon 3 (coding exon 3) of the IQSEC2 gene. This alteration results from a G to C substitution at nucleotide position 746, causing the glycine (G) at amino acid position 249 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual disability, X-linked 1

Uncertain:1

Dec 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 249 of the IQSEC2 protein (p.Gly249Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IQSEC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 521369). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IQSEC2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Aug 02, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

IQSEC2-related disorder

Uncertain:1

Apr 23, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The IQSEC2 c.746G>C variant is predicted to result in the amino acid substitution p.Gly249Ala. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

(source)

DANN

Uncertain

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;.;D;D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.22

T;T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

3.3

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.8

.;D;.;D;.

REVEL

Benign

0.091

Sift

Pathogenic

0.0

.;D;.;T;.

Sift4G

Benign

0.26

.;T;.;T;.

Polyphen

0.93

.;.;.;P;.

Vest4

0.30, 0.36

MutPred

0.076

Gain of glycosylation at S254 (P = 0.1253);Gain of glycosylation at S254 (P = 0.1253);Gain of glycosylation at S254 (P = 0.1253);.;.;

MVP

0.30

MPC

1.2

ClinPred

0.78

GERP RS

5.1

Varity_R

0.76

gMVP

0.47

Mutation Taster

=71/29

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over