rs782357394

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001111125.3(IQSEC2):c.578G>C(p.Gly193Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,154,368 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., 6 hem., cov: 24)

Exomes 𝑓: 0.00054 ( 0 hom. 163 hem. )

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.01

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06268445).

BP6

Variant X-53320546-C-G is Benign according to our data. Variant chrX-53320546-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 379876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53320546-C-G is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 link	c.578G>C	p.Gly193Ala	missense_variant	Exon 1 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.578G>C	p.Gly193Ala	missense_variant	Exon 1 of 15		NM_001111125.3	ENSP00000495726.1		Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

112458

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

AN XY:

34700

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000927

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:

0.000509

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000368

AC:

AN:

92344

Hom.:

AF XY:

0.000398

AC XY:

AN XY:

30122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000887

Gnomad NFE exome

AF:

0.000991

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000538

AC:

561

AN:

1041865

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

163

AN XY:

337679

show subpopulations

Gnomad4 AFR exome

AF:

0.0000425

Gnomad4 AMR exome

AF:

0.0000369

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000272

Gnomad4 NFE exome

AF:

0.000673

Gnomad4 OTH exome

AF:

0.000228

GnomAD4 genome

AF:

0.000276

AC:

AN:

112503

Hom.:

Cov.:

AF XY:

0.000173

AC XY:

AN XY:

34755

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000926

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000509

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000212

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Mar 06, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

IQSEC2: PP2, BS2 -

not specified

Benign:1

Aug 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Intellectual disability, X-linked 1

Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jan 16, 2019

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

Jul 15, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.013

.;T;T

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.83

T;.;T

M_CAP

Benign

0.063

MetaRNN

Benign

0.063

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.040

.;N;.

REVEL

Benign

0.070

Sift

Uncertain

0.0040

.;D;.

Sift4G

Benign

0.31

.;T;.

Vest4

0.18

MVP

0.25

MPC

1.2

ClinPred

0.14

GERP RS

3.0

Varity_R

0.17

gMVP

0.41

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over