X-53234582-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001111125.3(IQSEC2):c.4104G>A(p.Leu1368=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,118,294 control chromosomes in the GnomAD database, including 1,164 homozygotes. There are 3,431 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.067 (651 hom., 1583 hem., cov: 20)
  • Exomes 𝑓: 0.0071 (513 hom. 1848 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0530

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant X-53234582-C-T is Benign according to our data. Variant chrX-53234582-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 93557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.053 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.4104G>A	p.Leu1368=	synonymous_variant	15/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4104G>A	p.Leu1368=	synonymous_variant	15/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes AF: 0.0668 AC: 7131 AN: 106704 Hom.: 653 Cov.: 20 AF XY: 0.0530 AC XY: 1570 AN XY: 29610

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.00536

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000890

Gnomad OTH AF: 0.0519

GnomAD3 exomes AF: 0.0221 AC: 1677 AN: 75764 Hom.: 119 AF XY: 0.0196 AC XY: 387 AN XY: 19772

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00343

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000308

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.00708 AC: 7164 AN: 1011557 Hom.: 513 Cov.: 34 AF XY: 0.00577 AC XY: 1848 AN XY: 320513

Gnomad4 AFR exome AF: 0.236

Gnomad4 AMR exome AF: 0.0142

Gnomad4 ASJ exome AF: 0.00540

Gnomad4 EAS exome AF: 0.0000374

Gnomad4 SAS exome AF: 0.000604

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000438

Gnomad4 OTH exome AF: 0.0169

GnomAD4 genome AF: 0.0669 AC: 7138 AN: 106737 Hom.: 651 Cov.: 20 AF XY: 0.0534 AC XY: 1583 AN XY: 29653

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.00536

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000890

Gnomad4 OTH AF: 0.0513

Alfa AF: 0.0351 Hom.: 215

Bravo AF: 0.0786

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 15, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2016	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2016

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. -

Intellectual disability, X-linked 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	5.5
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs184087864; hg19: chrX-53263764; COSMIC: COSV64723217; COSMIC: COSV64723217;