rs371450118

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001111125.3(IQSEC2):c.3990G>A(p.Gly1330Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,134,560 control chromosomes in the GnomAD database, including 8 homozygotes. There are 322 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., 41 hem., cov: 20)

Exomes 𝑓: 0.00087 ( 8 hom. 281 hem. )

Consequence

IQSEC2
NM_001111125.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0350

Publications

2 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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant X-53234696-C-T is Benign according to our data. Variant chrX-53234696-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 129282.

BP7

Synonymous conserved (PhyloP=-0.035 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00124 (135/108962) while in subpopulation EAS AF = 0.024 (82/3417). AF 95% confidence interval is 0.0198. There are 0 homozygotes in GnomAd4. There are 41 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 41 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 link	c.3990G>A	p.Gly1330Gly	synonymous_variant	Exon 15 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.3990G>A	p.Gly1330Gly	synonymous_variant	Exon 15 of 15		NM_001111125.3	ENSP00000495726.1		Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

136

AN:

108916

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000572

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00135

Gnomad ASJ

AF:

0.00268

Gnomad EAS

AF:

0.0239

Gnomad SAS

AF:

0.00120

Gnomad FIN

AF:

0.000175

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000134

Gnomad OTH

AF:

0.00345

GnomAD2 exomes

AF:

0.00352

AC:

295

AN:

83837

AF XY:

0.00338

show subpopulations

Gnomad AFR exome

AF:

0.000880

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.000564

Gnomad EAS exome

AF:

0.0311

Gnomad FIN exome

AF:

0.000101

Gnomad NFE exome

AF:

0.000189

Gnomad OTH exome

AF:

0.00366

GnomAD4 exome

AF:

0.000871

AC:

893

AN:

1025598

Hom.:

Cov.:

AF XY:

0.000861

AC XY:

281

AN XY:

326264

show subpopulations

African (AFR)

AF:

0.000372

AC:

AN:

24218

American (AMR)

AF:

0.00212

AC:

AN:

24479

Ashkenazi Jewish (ASJ)

AF:

0.00121

AC:

AN:

16558

East Asian (EAS)

AF:

0.0187

AC:

502

AN:

26889

South Asian (SAS)

AF:

0.00124

AC:

AN:

45009

European-Finnish (FIN)

AF:

0.0000552

AC:

AN:

36247

Middle Eastern (MID)

AF:

0.000515

AC:

AN:

3884

European-Non Finnish (NFE)

AF:

0.000139

AC:

112

AN:

805257

Other (OTH)

AF:

0.00321

AC:

138

AN:

43057

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00124

AC:

135

AN:

108962

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

31350

show subpopulations

African (AFR)

AF:

0.000570

AC:

AN:

29801

American (AMR)

AF:

0.00125

AC:

AN:

10371

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

2610

East Asian (EAS)

AF:

0.0240

AC:

AN:

3417

South Asian (SAS)

AF:

0.00121

AC:

AN:

2486

European-Finnish (FIN)

AF:

0.000175

AC:

AN:

5719

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.000134

AC:

AN:

52216

Other (OTH)

AF:

0.00341

AC:

AN:

1467

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.000870

Hom.:

Bravo

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Dec 03, 2013

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 14, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Intellectual disability, X-linked 1

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 14, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

IQSEC2-related disorder

Benign:1

May 20, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

3.9

(source)

DANN

Benign

0.75

PhyloP100

-0.035

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over