Variant X-53234256-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_001111125.3(IQSEC2):c.4430C>T(p.Pro1477Leu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 16)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.29

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 Likely_benign. Variant got -1 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27767754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3 linkuse as main transcript	c.4430C>T	p.Pro1477Leu	missense_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.4430C>T	p.Pro1477Leu	missense_variant	15/15		NM_001111125.3	P1	Q5JU85-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

983715

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

298133

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, X-linked 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2023

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1477 of the IQSEC2 protein (p.Pro1477Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IQSEC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1206978). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt IQSEC2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 20, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Uncertain

DANN

Uncertain

0.99

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

.;T

M_CAP

Uncertain

0.098

MetaRNN

Benign

0.28

T;T

MetaSVM

Benign

-1.0

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-1.5

N;.

REVEL

Benign

0.20

Sift

Pathogenic

0.0

D;.

Sift4G

Uncertain

0.019

D;.

Vest4

0.30

MutPred

0.24

Loss of glycosylation at P1477 (P = 0.0076);Loss of glycosylation at P1477 (P = 0.0076);

MVP

0.30

MPC

1.1

ClinPred

0.95

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.18

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over