rs782697291

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001111125.3(IQSEC2):​c.3364C>T​(p.Arg1122Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,203,945 control chromosomes in the GnomAD database, including 2 homozygotes. There are 173 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 0.00011 ( 0 hom., 5 hem., cov: 24)
Exomes 𝑓: 0.00027 ( 2 hom. 168 hem. )

Consequence

IQSEC2
NM_001111125.3 missense

Scores

4
6
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:4

Conservation

PhyloP100: 2.15
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.010379791).
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000106 (12/112914) while in subpopulation SAS AF= 0.00289 (8/2769). AF 95% confidence interval is 0.00144. There are 0 homozygotes in gnomad4. There are 5 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
IQSEC2NM_001111125.3 linkc.3364C>T p.Arg1122Cys missense_variant Exon 13 of 15 ENST00000642864.1 NP_001104595.1 Q5JU85-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
IQSEC2ENST00000642864.1 linkc.3364C>T p.Arg1122Cys missense_variant Exon 13 of 15 NM_001111125.3 ENSP00000495726.1 Q5JU85-2

Frequencies

GnomAD3 genomes
AF:
0.000106
AC:
12
AN:
112863
Hom.:
0
Cov.:
24
AF XY:
0.000143
AC XY:
5
AN XY:
35019
show subpopulations
Gnomad AFR
AF:
0.0000643
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00288
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000376
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000403
AC:
67
AN:
166346
Hom.:
0
AF XY:
0.000739
AC XY:
40
AN XY:
54160
show subpopulations
Gnomad AFR exome
AF:
0.0000844
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00373
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000413
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000269
AC:
293
AN:
1091031
Hom.:
2
Cov.:
32
AF XY:
0.000470
AC XY:
168
AN XY:
357533
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000289
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00364
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000104
Gnomad4 OTH exome
AF:
0.000262
GnomAD4 genome
AF:
0.000106
AC:
12
AN:
112914
Hom.:
0
Cov.:
24
AF XY:
0.000143
AC XY:
5
AN XY:
35080
show subpopulations
Gnomad4 AFR
AF:
0.0000641
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00289
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000376
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
2
Bravo
AF:
0.0000264
ExAC
AF:
0.000471
AC:
57

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Abnormal brain morphology Pathogenic:1
Likely pathogenic, criteria provided, single submitterresearchLupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine-- -
not specified Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsNov 21, 2019- -
Intellectual disability, X-linked 1 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2024- -
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 31, 2017This 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. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJan 01, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Benign
-0.20
T
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Pathogenic
1.0
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.98
D;D;D;.;D;D
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.010
T;T;T;T;T;T
MetaSVM
Benign
-0.42
T
PrimateAI
Pathogenic
0.81
D
PROVEAN
Pathogenic
-5.5
.;.;.;D;.;D
REVEL
Benign
0.26
Sift
Uncertain
0.012
.;.;.;D;.;D
Sift4G
Uncertain
0.0020
.;.;.;D;.;T
Polyphen
1.0
.;.;.;.;.;D
Vest4
0.20, 0.55
MutPred
0.26
.;.;Gain of catalytic residue at M1120 (P = 0.0011);Gain of catalytic residue at M1120 (P = 0.0011);Gain of catalytic residue at M1120 (P = 0.0011);.;
MVP
0.71
MPC
2.6
ClinPred
0.82
D
GERP RS
5.1
Varity_R
0.35
gMVP
0.78

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.

Other links and lift over

dbSNP: rs782697291; hg19: chrX-53265591; API