X-53234247-T-TTGGCC

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PM4 PP5_Moderate

The NM_001111125.3(IQSEC2):c.4438_4439insGGCCA(p.Lys1480ArgfsTer17) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 16)
• Consequence: IQSEC2 NM_001111125.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.13

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Frameshift in the end of transcript resulting in stoplost. Downstream stopcodon found after 1606 codons.
• PP5: Variant X-53234247-T-TTGGCC is Pathogenic according to our data. Variant chrX-53234247-T-TTGGCC is described in ClinVar as [Pathogenic]. Clinvar id is 471275.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.4438_4439insGGCCA	p.Lys1480ArgfsTer17	frameshift_variant	15/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4438_4439insGGCCA	p.Lys1480ArgfsTer17	frameshift_variant	15/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes Cov.: 16

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 16

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 31, 2017

Family studies have indicated that this variant was not present in the parents of an individual with clinical features consistent with an IQSEC2-related condition, which suggests that it was de novo in that affected individual (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with IQSEC2-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change inserts 5 nucleotides in exon 15 of the IQSEC2 mRNA (c.4434_4438dupGGCCA), causing a frameshift at codon 1480 (p.Lys1480Argfs*17). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acids and extend the length of the IQSEC2 protein by 7 additional amino acids. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556858912; hg19: chrX-53263429;