X-53236386-G-C

Position:

• chrX-53236386-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001111125.3(IQSEC2):​c.3387C>G​(p.Tyr1129Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 24)
• Consequence: IQSEC2 NM_001111125.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.331

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53236386-G-C is Pathogenic according to our data. Variant chrX-53236386-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 1075324.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.3387C>G	p.Tyr1129Ter	stop_gained	13/15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.3387C>G	p.Tyr1129Ter	stop_gained	13/15		NM_001111125.3	ENSP00000495726	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

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

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

This sequence change creates a premature translational stop signal (p.Tyr1129*) in the IQSEC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in IQSEC2 are known to be pathogenic (PMID: 21686261, 26793055, 27665735). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with IQSEC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1075324). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.49	N
MutationTaster	Benign	1.0	A;A;A
Vest4		0.41, 0.26
GERP RS		-0.073

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-53265568;