rs782439813

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001111125.3(IQSEC2):c.596C>T(p.Pro199Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,155,970 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 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. P199Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 24)

Exomes 𝑓: 0.00011 ( 0 hom. 44 hem. )

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.740

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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10274696).

BP6

Variant X-53320528-G-A is Benign according to our data. Variant chrX-53320528-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 418260.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 link	c.596C>T	p.Pro199Leu	missense_variant	Exon 1 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1 link	c.596C>T	p.Pro199Leu	missense_variant	Exon 1 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes

AF:

0.0000978

AC:

AN:

112495

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000127

AC:

AN:

94850

AF XY:

0.000193

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000552

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000321

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000112

AC:

117

AN:

1043475

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

338621

show subpopulations

African (AFR)

AF:

0.0000422

AC:

AN:

23688

American (AMR)

AF:

0.0000366

AC:

AN:

27316

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18230

East Asian (EAS)

AF:

0.00

AC:

AN:

26078

South Asian (SAS)

AF:

0.00

AC:

AN:

49108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36769

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2940

European-Non Finnish (NFE)

AF:

0.000137

AC:

112

AN:

815483

Other (OTH)

AF:

0.0000684

AC:

AN:

43863

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.534

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:

0.0000978

AC:

AN:

112495

Hom.:

Cov.:

AF XY:

0.0000865

AC XY:

AN XY:

34693

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31083

American (AMR)

AF:

0.00

AC:

AN:

10795

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2644

East Asian (EAS)

AF:

0.00

AC:

AN:

3523

South Asian (SAS)

AF:

0.00

AC:

AN:

2774

European-Finnish (FIN)

AF:

0.000161

AC:

AN:

6195

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.000189

AC:

AN:

53042

Other (OTH)

AF:

0.00

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.544

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:

0.0000604

ExAC

AF:

0.000103

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 1

Uncertain:1Benign:2

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 13, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

not specified

Uncertain:1

Jul 26, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 22, 2020

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Feb 09, 2021

GeneDx

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

Benign

0.11

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.042

.;T;T

FATHMM_MKL

Benign

0.24

LIST_S2

Uncertain

0.86

D;.;D

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.10

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

.;N;N

PhyloP100

0.74

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.8

.;N;.

REVEL

Benign

0.078

Sift

Uncertain

0.010

.;D;.

Sift4G

Benign

0.077

.;T;.

Vest4

0.10

MutPred

0.27

Loss of glycosylation at P199 (P = 0.0143);Loss of glycosylation at P199 (P = 0.0143);Loss of glycosylation at P199 (P = 0.0143);

MVP

0.47

MPC

1.3

ClinPred

0.18

GERP RS

3.1

Varity_R

0.13

gMVP

0.23

Mutation Taster

=90/10

polymorphism

(source)

Splicing

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