rs1556861372
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_001111125.3(IQSEC2):c.2777G>A(p.Arg926Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,063,512 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 22)
Exomes 𝑓: 0.000029 ( 0 hom. 9 hem. )
Consequence
IQSEC2
NM_001111125.3 missense
NM_001111125.3 missense
Scores
4
3
4
Clinical Significance
Conservation
PhyloP100: 7.83
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP6
?
Variant X-53243444-C-T is Benign according to our data. Variant chrX-53243444-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 538608.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
BS2
?
High Hemizygotes in GnomAdExome4 at 9 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
IQSEC2 | NM_001111125.3 | c.2777G>A | p.Arg926Gln | missense_variant | 9/15 | ENST00000642864.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
IQSEC2 | ENST00000642864.1 | c.2777G>A | p.Arg926Gln | missense_variant | 9/15 | NM_001111125.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
GnomAD3 exomes AF: 0.0000234 AC: 3AN: 127956Hom.: 0 AF XY: 0.0000252 AC XY: 1AN XY: 39610
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GnomAD4 exome AF: 0.0000291 AC: 31AN: 1063512Hom.: 0 Cov.: 30 AF XY: 0.0000261 AC XY: 9AN XY: 345336
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GnomAD4 genome ? Cov.: 22
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Intellectual disability, X-linked 1 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 2022 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanism of disease in this gene and are associated with IQSEC2-related intellectual disability (MIM# 309530). Loss of function has been demonstrated as the predominant disease mechanism for this gene, however some missense variants have been shown to impair GTP binding and cause the constitutively active protein activity (PMID: 20473311, PMID: 30842726). (I) 0110 - This gene is associated with X-linked disease. Males present with a severe early-onset condition, whereas females have a more variable phenotype, which tends be milder with a later onset, and they can also be asymptomatic carriers (PMID: 30206421). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0253 - This variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a X-linked condition (2 heterozygotes, 0 homozygotes, 1 hemizygote). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated Sec7 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been classified as a VUS (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2022 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;.;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
Polyphen
1.0
.;.;.;D
Vest4
0.50, 0.57
MutPred
Loss of disorder (P = 0.227);Loss of disorder (P = 0.227);Loss of disorder (P = 0.227);.;
MVP
0.64
MPC
2.2
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at