X-53234696-C-T

Position:

chrX-53234696-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_001111125.3(IQSEC2):c.3990G>A(p.Gly1330=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000906 in 1,134,560 control chromosomes in the GnomAD database, including 8 homozygotes. There are 322 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 0.0012 ( 0 hom., 41 hem., cov: 20)

Exomes 𝑓: 0.00087 ( 8 hom. 281 hem. )

Consequence

IQSEC2
NM_001111125.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.0350

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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant X-53234696-C-T is Benign according to our data. Variant chrX-53234696-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129282.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}. Variant chrX-53234696-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.035 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00124 (135/108962) while in subpopulation EAS AF= 0.024 (82/3417). AF 95% confidence interval is 0.0198. There are 0 homozygotes in gnomad4. There are 41 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 41 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3 linkuse as main transcript	c.3990G>A	p.Gly1330=	synonymous_variant	15/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1 linkuse as main transcript	c.3990G>A	p.Gly1330=	synonymous_variant	15/15		NM_001111125.3	P1	Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

136

AN:

108916

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

31294

show subpopulations

Gnomad AFR

AF:

0.000572

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00135

Gnomad ASJ

AF:

0.00268

Gnomad EAS

AF:

0.0239

Gnomad SAS

AF:

0.00120

Gnomad FIN

AF:

0.000175

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000134

Gnomad OTH

AF:

0.00345

GnomAD3 exomes

AF:

0.00352

AC:

295

AN:

83837

Hom.:

AF XY:

0.00338

AC XY:

AN XY:

21873

show subpopulations

Gnomad AFR exome

AF:

0.000880

Gnomad AMR exome

AF:

0.00240

Gnomad ASJ exome

AF:

0.000564

Gnomad EAS exome

AF:

0.0311

Gnomad SAS exome

AF:

0.000772

Gnomad FIN exome

AF:

0.000101

Gnomad NFE exome

AF:

0.000189

Gnomad OTH exome

AF:

0.00366

GnomAD4 exome

AF:

0.000871

AC:

893

AN:

1025598

Hom.:

Cov.:

AF XY:

0.000861

AC XY:

281

AN XY:

326264

show subpopulations

Gnomad4 AFR exome

AF:

0.000372

Gnomad4 AMR exome

AF:

0.00212

Gnomad4 ASJ exome

AF:

0.00121

Gnomad4 EAS exome

AF:

0.0187

Gnomad4 SAS exome

AF:

0.00124

Gnomad4 FIN exome

AF:

0.0000552

Gnomad4 NFE exome

AF:

0.000139

Gnomad4 OTH exome

AF:

0.00321

GnomAD4 genome

AF:

0.00124

AC:

135

AN:

108962

Hom.:

Cov.:

AF XY:

0.00131

AC XY:

AN XY:

31350

show subpopulations

Gnomad4 AFR

AF:

0.000570

Gnomad4 AMR

AF:

0.00125

Gnomad4 ASJ

AF:

0.00268

Gnomad4 EAS

AF:

0.0240

Gnomad4 SAS

AF:

0.00121

Gnomad4 FIN

AF:

0.000175

Gnomad4 NFE

AF:

0.000134

Gnomad4 OTH

AF:

0.00341

Alfa

AF:

0.000870

Hom.:

Bravo

AF:

0.00178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 03, 2013

- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 14, 2016

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. -

Intellectual disability, X-linked 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 14, 2016

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

3.9

DANN

Benign

0.75

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

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