rs782697291

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001111125.3(IQSEC2):c.3364C>T(p.Arg1122Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,203,945 control chromosomes in the GnomAD database, including 2 homozygotes. There are 173 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1122H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 5 hem., cov: 24)

Exomes 𝑓: 0.00027 ( 2 hom. 168 hem. )

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.15

Publications

7 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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010379791).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000106 (12/112914) while in subpopulation SAS AF = 0.00289 (8/2769). AF 95% confidence interval is 0.00144. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 link	c.3364C>T	p.Arg1122Cys	missense_variant	Exon 13 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.3364C>T	p.Arg1122Cys	missense_variant	Exon 13 of 15		NM_001111125.3	ENSP00000495726.1		Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.000106

AC:

AN:

112863

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000643

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00288

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000403

AC:

AN:

166346

AF XY:

0.000739

show subpopulations

Gnomad AFR exome

AF:

0.0000844

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000413

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000269

AC:

293

AN:

1091031

Hom.:

Cov.:

AF XY:

0.000470

AC XY:

168

AN XY:

357533

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26266

American (AMR)

AF:

0.0000289

AC:

AN:

34590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19233

East Asian (EAS)

AF:

0.00

AC:

AN:

29920

South Asian (SAS)

AF:

0.00364

AC:

192

AN:

52692

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39979

Middle Eastern (MID)

AF:

0.000242

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.000104

AC:

AN:

838406

Other (OTH)

AF:

0.000262

AC:

AN:

45820

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000106

AC:

AN:

112914

Hom.:

Cov.:

AF XY:

0.000143

AC XY:

AN XY:

35080

show subpopulations

African (AFR)

AF:

0.0000641

AC:

AN:

31177

American (AMR)

AF:

0.00

AC:

AN:

10818

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2660

East Asian (EAS)

AF:

0.00

AC:

AN:

3563

South Asian (SAS)

AF:

0.00289

AC:

AN:

2769

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6267

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000376

AC:

AN:

53210

Other (OTH)

AF:

0.00

AC:

AN:

1549

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

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:

0.000174

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000471

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Benign:1

Nov 21, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, X-linked 1

Benign:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Mar 31, 2017

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. -

not provided

Benign:1

Jan 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.98

D;D;D;.;D;D

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.010

T;T;T;T;T;T

MetaSVM

Benign

-0.42

PhyloP100

2.1

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.5

.;.;.;D;.;D

REVEL

Benign

0.26

Sift

Uncertain

0.012

.;.;.;D;.;D

Sift4G

Uncertain

0.0020

.;.;.;D;.;T

Polyphen

1.0

.;.;.;.;.;D

Vest4

0.20, 0.55

MutPred

0.26

.;.;Gain of catalytic residue at M1120 (P = 0.0011);Gain of catalytic residue at M1120 (P = 0.0011);Gain of catalytic residue at M1120 (P = 0.0011);.;

MVP

0.71

MPC

2.6

ClinPred

0.82

GERP RS

5.1

Varity_R

0.35

gMVP

0.78

Mutation Taster

=80/20

disease causing (ClinVar)

(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