rs587780359

Variant names:

• chrX-53320923-C-G
• rs587780359
• NM_001111125.3:c.201G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_001111125.3(IQSEC2):​c.201G>C​(p.Leu67Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.19
• Publications: 0 publications found

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]

IQSEC2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• intellectual disability, X-linked 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-53320923-C-G is Benign according to our data. Variant chrX-53320923-C-G is described in CliVar as Benign. Clinvar id is 129281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53320923-C-G is described in CliVar as Benign. Clinvar id is 129281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53320923-C-G is described in CliVar as Benign. Clinvar id is 129281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53320923-C-G is described in CliVar as Benign. Clinvar id is 129281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53320923-C-G is described in CliVar as Benign. Clinvar id is 129281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53320923-C-G is described in CliVar as Benign. Clinvar id is 129281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53320923-C-G is described in CliVar as Benign. Clinvar id is 129281.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-53320923-C-G is described in CliVar as Benign. Clinvar id is 129281.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.19 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.201G>C	p.Leu67Leu	synonymous_variant	Exon 1 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.201G>C	p.Leu67Leu	synonymous_variant	Exon 1 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 25, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		1.2
PromoterAI		0.042	Neutral

Splicing

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

Other links and lift over

dbSNP: rs587780359; hg19: chrX-53350121;