rs797045140

chrX-53238307-CTG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001111125.3(IQSEC2):c.3116-3_3116-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 21)
• Consequence: IQSEC2 NM_001111125.3 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.99

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.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.036042087 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.9, offset of 0 (no position change), new splice context is: ccagtctcccctttctccAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-53238307-CTG-C is Pathogenic according to our data. Variant chrX-53238307-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 208858.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53238307-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.3116-3_3116-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.3116-3_3116-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001111125.3	P1

Frequencies

GnomAD3 genomes Cov.: 21

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 21

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

Serv. Biochemistry and Molecular genetics, Hospital Clinic de Barcelona, Hospital Clínic de Barcelona

May 01, 2014

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs797045140; hg19: chrX-53267489;