X-53255812-C-G

Variant names:

• chrX-53255812-C-G
• NM_001111125.3:c.987G>C
• IQSEC2 p.Leu329Leu

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001111125.3(IQSEC2):​c.987G>C​(p.Leu329Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L329L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.925
• 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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP7: Synonymous conserved (PhyloP=0.925 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	NM_001111125.3	MANE Select	c.987G>C	p.Leu329Leu	synonymous	Exon 3 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001441092.1		c.987G>C	p.Leu329Leu	synonymous	Exon 3 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.987G>C	p.Leu329Leu	synonymous	Exon 3 of 14	NP_001397665.1	A0A1W2PR28

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.987G>C	p.Leu329Leu	synonymous	Exon 3 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.372G>C	p.Leu124Leu	synonymous	Exon 3 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000638630.1	TSL:1	c.276G>C	p.Leu92Leu	synonymous	Exon 2 of 4	ENSP00000492390.1	A0A1W2PR18

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.4
DANN	Benign	0.60
PhyloP100		0.93

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-53284994;