rs782439813

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_001111125.3(IQSEC2):​c.596C>T​(p.Pro199Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,155,970 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 47 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 0.000098 ( 0 hom., 3 hem., cov: 24)
Exomes 𝑓: 0.00011 ( 0 hom. 44 hem. )

Consequence

IQSEC2
NM_001111125.3 missense

Scores

1
4
12

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 0.740
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 -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.10274696).
BP6
Variant X-53320528-G-A is Benign according to our data. Variant chrX-53320528-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418260.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=2}.
BS2
High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
IQSEC2NM_001111125.3 linkuse as main transcriptc.596C>T p.Pro199Leu missense_variant 1/15 ENST00000642864.1 NP_001104595.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
IQSEC2ENST00000642864.1 linkuse as main transcriptc.596C>T p.Pro199Leu missense_variant 1/15 NM_001111125.3 ENSP00000495726 P1Q5JU85-2

Frequencies

GnomAD3 genomes
AF:
0.0000978
AC:
11
AN:
112495
Hom.:
0
Cov.:
24
AF XY:
0.0000865
AC XY:
3
AN XY:
34693
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000161
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000189
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000127
AC:
12
AN:
94850
Hom.:
0
AF XY:
0.000193
AC XY:
6
AN XY:
31064
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000552
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:
0.000321
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000112
AC:
117
AN:
1043475
Hom.:
0
Cov.:
31
AF XY:
0.000130
AC XY:
44
AN XY:
338621
show subpopulations
Gnomad4 AFR exome
AF:
0.0000422
Gnomad4 AMR exome
AF:
0.0000366
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:
0.000137
Gnomad4 OTH exome
AF:
0.0000684
GnomAD4 genome
AF:
0.0000978
AC:
11
AN:
112495
Hom.:
0
Cov.:
24
AF XY:
0.0000865
AC XY:
3
AN XY:
34693
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000161
Gnomad4 NFE
AF:
0.000189
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000174
Hom.:
1
Bravo
AF:
0.0000604
ExAC
AF:
0.000103
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Intellectual disability, X-linked 1 Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 16, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenetic Services Laboratory, University of ChicagoJul 26, 2017- -
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 22, 2020This 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. -
not provided Benign:1
Likely benign, criteria provided, single submitterclinical testingGeneDxFeb 09, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.54
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.042
.;T;T
FATHMM_MKL
Benign
0.24
N
LIST_S2
Uncertain
0.86
D;.;D
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.10
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
.;N;N
MutationTaster
Benign
0.99
D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.8
.;N;.
REVEL
Benign
0.078
Sift
Uncertain
0.010
.;D;.
Sift4G
Benign
0.077
.;T;.
Vest4
0.10
MutPred
0.27
Loss of glycosylation at P199 (P = 0.0143);Loss of glycosylation at P199 (P = 0.0143);Loss of glycosylation at P199 (P = 0.0143);
MVP
0.47
MPC
1.3
ClinPred
0.18
T
GERP RS
3.1
Varity_R
0.13
gMVP
0.23

Splicing

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: rs782439813; hg19: chrX-53349726; API