rs368559547

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_001111125.3(IQSEC2):c.803C>G(p.Pro268Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000444 in 112,618 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P268H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000019 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.68

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.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24374515).

BP6

Variant X-53255996-G-C is Benign according to our data. Variant chrX-53255996-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1442992.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3 linkuse as main transcript	c.803C>G	p.Pro268Arg	missense_variant	3/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1 linkuse as main transcript	c.803C>G	p.Pro268Arg	missense_variant	3/15		NM_001111125.3	P1	Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.0000444

AC:

AN:

112618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34776

show subpopulations

Gnomad AFR

AF:

0.000161

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

GnomAD3 exomes

AF:

0.00000704

AC:

AN:

142023

Hom.:

AF XY:

0.00

AC XY:

AN XY:

40759

show subpopulations

Gnomad AFR exome

AF:

0.000104

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000186

AC:

AN:

1076141

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

346813

show subpopulations

Gnomad4 AFR exome

AF:

0.0000770

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

AF:

0.0000444

AC:

AN:

112618

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34776

show subpopulations

Gnomad4 AFR

AF:

0.000161

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2018

The p.P268R variant (also known as c.803C>G), located in coding exon 3 of the IQSEC2 gene, results from a C to G substitution at nucleotide position 803. The proline at codon 268 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Intellectual disability, X-linked 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 28, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.34

BayesDel_addAF

Benign

-0.0017

BayesDel_noAF

Uncertain

-0.020

Cadd

Uncertain

Dann

Uncertain

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.86

D;.;D;D;D

M_CAP

Benign

0.061

MetaRNN

Benign

0.24

T;T;T;T;T

MetaSVM

Benign

-0.51

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Uncertain

0.76

Polyphen

0.98

.;.;.;D;.

Vest4

0.15, 0.14

MutPred

0.15

Loss of glycosylation at P268 (P = 0.0127);Loss of glycosylation at P268 (P = 0.0127);Loss of glycosylation at P268 (P = 0.0127);.;.;

MVP

0.82

MPC

1.5

ClinPred

0.28

GERP RS

5.1

Varity_R

0.34

gMVP

0.49

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