rs782748026

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001111125.3(IQSEC2):c.1926G>A(p.Pro642Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000232 in 1,207,288 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 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 0.00013 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000012 ( 0 hom. 3 hem. )

Consequence

IQSEC2
NM_001111125.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.69

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant X-53250650-C-T is Benign according to our data. Variant chrX-53250650-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197718.

BP7

Synonymous conserved (PhyloP=-1.69 with no splicing effect.

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.1926G>A	p.Pro642Pro	synonymous_variant	Exon 5 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.1926G>A	p.Pro642Pro	synonymous_variant	Exon 5 of 15		NM_001111125.3	ENSP00000495726.1		Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.000134

AC:

AN:

111939

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000487

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000454

AC:

AN:

176058

AF XY:

0.0000315

show subpopulations

Gnomad AFR exome

AF:

0.000674

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000119

AC:

AN:

1095349

Hom.:

Cov.:

AF XY:

0.00000830

AC XY:

AN XY:

361305

show subpopulations

African (AFR)

AF:

0.000341

AC:

AN:

26378

American (AMR)

AF:

0.00

AC:

AN:

35148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19285

East Asian (EAS)

AF:

0.00

AC:

AN:

30159

South Asian (SAS)

AF:

0.00

AC:

AN:

54014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39501

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4124

European-Non Finnish (NFE)

AF:

0.00000357

AC:

AN:

840810

Other (OTH)

AF:

0.0000218

AC:

AN:

45930

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.000134

AC:

AN:

111939

Hom.:

Cov.:

AF XY:

0.000146

AC XY:

AN XY:

34133

show subpopulations

African (AFR)

AF:

0.000487

AC:

AN:

30780

American (AMR)

AF:

0.00

AC:

AN:

10673

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2638

East Asian (EAS)

AF:

0.00

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2725

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53052

Other (OTH)

AF:

0.00

AC:

AN:

1508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

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:

0.0000712

Hom.:

Bravo

AF:

0.000166

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Oct 01, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 11, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, X-linked 1

Benign:1

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jul 09, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.94

(source)

DANN

Benign

0.48

PhyloP100

-1.7

PromoterAI

-0.015

Neutral

(source)

Mutation Taster

=100/0

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over