chrX-53234266-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_001111125.3(IQSEC2):​c.4419del​(p.Ser1474ValfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000265 in 829,857 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (β˜…β˜…). Synonymous variant affecting the same amino acid position (i.e. P1473P) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 15)
Exomes 𝑓: 0.000027 ( 0 hom. 0 hem. )

Consequence

IQSEC2
NM_001111125.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.16
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PP5
Variant X-53234266-TG-T is Pathogenic according to our data. Variant chrX-53234266-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 599453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
IQSEC2NM_001111125.3 linkuse as main transcriptc.4419del p.Ser1474ValfsTer21 frameshift_variant 15/15 ENST00000642864.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
IQSEC2ENST00000642864.1 linkuse as main transcriptc.4419del p.Ser1474ValfsTer21 frameshift_variant 15/15 NM_001111125.3 P1Q5JU85-2

Frequencies

GnomAD3 genomes
Cov.:
15
GnomAD3 exomes
AF:
0.000180
AC:
9
AN:
50130
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
8622
show subpopulations
Gnomad AFR exome
AF:
0.000387
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.000847
Gnomad EAS exome
AF:
0.000329
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000974
Gnomad NFE exome
AF:
0.000173
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000265
AC:
22
AN:
829857
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
235173
show subpopulations
Gnomad4 AFR exome
AF:
0.0000556
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.000279
Gnomad4 EAS exome
AF:
0.0000731
Gnomad4 SAS exome
AF:
0.0000325
Gnomad4 FIN exome
AF:
0.0000813
Gnomad4 NFE exome
AF:
0.0000132
Gnomad4 OTH exome
AF:
0.0000936
GnomAD4 genome
Cov.:
15
Alfa
AF:
0.00102
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Intellectual disability, X-linked 1 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInstitute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's HospitalFeb 15, 2018PVS1, PS2; This variant introduces a single-base-pair deletion in the coding sequence of the IQSEC2 gene, which leads to a shift in the protein reading frame and introduces of a premature termination codon in a gene where loss of function is a known mechanism of disease [ACMG: PVS1]. Sanger sequencing confirmed this to be a de novo alteration, as it was not detected in the submitted parental specimens (identity confirmed)[ACMG: PS2]. No evidence was found to support any of the ACMG Benign criteria; therefore, this alteration meets ACMG guidelines for classification as a pathogenic variant. -
Pathogenic, criteria provided, single submitterclinical testingMendelicsMay 04, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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: rs1569290954; hg19: chrX-53263448; API