X-53248188-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_001111125.3(IQSEC2):c.2508G>A(p.Ala836Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000609 in 1,207,872 control chromosomes in the GnomAD database, including 6 homozygotes. There are 270 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A836A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00077 ( 1 hom., 22 hem., cov: 22)

Exomes 𝑓: 0.00059 ( 5 hom. 248 hem. )

Consequence

IQSEC2
NM_001111125.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.455

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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.35).

BP6

Variant X-53248188-C-T is Benign according to our data. Variant chrX-53248188-C-T is described in ClinVar as [Benign]. Clinvar id is 386738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.455 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000772 (86/111426) while in subpopulation EAS AF = 0.00481 (17/3536). AF 95% confidence interval is 0.00306. There are 1 homozygotes in GnomAd4. There are 22 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 22 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 link	c.2508G>A	p.Ala836Ala	synonymous_variant	Exon 7 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.2508G>A	p.Ala836Ala	synonymous_variant	Exon 7 of 15		NM_001111125.3	ENSP00000495726.1		Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.000763

AC:

AN:

111376

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000765

Gnomad ASJ

AF:

0.0125

Gnomad EAS

AF:

0.00479

Gnomad SAS

AF:

0.00378

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00418

Gnomad NFE

AF:

0.000188

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00128

AC:

230

AN:

179162

AF XY:

0.00132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.0104

Gnomad EAS exome

AF:

0.00379

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000414

Gnomad OTH exome

AF:

0.00157

GnomAD4 exome

AF:

0.000593

AC:

650

AN:

1096446

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

248

AN XY:

361854

show subpopulations

African (AFR)

AF:

0.000190

AC:

AN:

26375

American (AMR)

AF:

0.0000854

AC:

AN:

35115

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

200

AN:

19365

East Asian (EAS)

AF:

0.00308

AC:

AN:

30169

South Asian (SAS)

AF:

0.00273

AC:

147

AN:

53779

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40434

Middle Eastern (MID)

AF:

0.00314

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000155

AC:

130

AN:

841040

Other (OTH)

AF:

0.00128

AC:

AN:

46035

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

105

131

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000772

AC:

AN:

111426

Hom.:

Cov.:

AF XY:

0.000654

AC XY:

AN XY:

33632

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30606

American (AMR)

AF:

0.000764

AC:

AN:

10477

Ashkenazi Jewish (ASJ)

AF:

0.0125

AC:

AN:

2647

East Asian (EAS)

AF:

0.00481

AC:

AN:

3536

South Asian (SAS)

AF:

0.00417

AC:

AN:

2639

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6056

Middle Eastern (MID)

AF:

0.00459

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000189

AC:

AN:

53048

Other (OTH)

AF:

0.00330

AC:

AN:

1515

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

Alfa

AF:

0.00167

Hom.:

Bravo

AF:

0.000895

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Feb 02, 2018

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. -

Inborn genetic diseases

Benign:1

Apr 27, 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. -

Intellectual disability, X-linked 1

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.2

(source)

DANN

Benign

0.77

PhyloP100

-0.46

PromoterAI

0.085

Neutral

(source)

Mutation Taster

=97/3

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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X-53248188-C-T

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