chrX-53320425-G-C

Variant names:

• chrX-53320425-G-C
• rs1411580863
• NM_001111125.3:c.699C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001111125.3(IQSEC2):​c.699C>G​(p.Leu233Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000043 in 1,163,865 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000029 (0 hom. 1 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.05
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant X-53320425-G-C is Benign according to our data. Variant chrX-53320425-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 538609.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.05 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	NM_001111125.3	MANE Select	c.699C>G	p.Leu233Leu	synonymous	Exon 1 of 15	NP_001104595.1
	IQSEC2	NM_001441092.1		c.699C>G	p.Leu233Leu	synonymous	Exon 1 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.699C>G	p.Leu233Leu	synonymous	Exon 1 of 14	NP_001397665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.699C>G	p.Leu233Leu	synonymous	Exon 1 of 15	ENSP00000495726.1
	IQSEC2	ENST00000706952.1		c.858C>G	p.Leu286Leu	synonymous	Exon 1 of 15	ENSP00000516672.1
	IQSEC2	ENST00000674510.1		c.699C>G	p.Leu233Leu	synonymous	Exon 1 of 15	ENSP00000502054.1

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112887 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000285 AC: 3 AN: 1050978 Hom.: 0 Cov.: 30 AF XY: 0.00000292 AC XY: 1 AN XY: 342254

African (AFR) AF: 0.00 AC: 0 AN: 24759

American (AMR) AF: 0.00 AC: 0 AN: 27867

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18584

East Asian (EAS) AF: 0.00 AC: 0 AN: 26998

South Asian (SAS) AF: 0.00 AC: 0 AN: 49789

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37541

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3737

European-Non Finnish (NFE) AF: 0.00000367 AC: 3 AN: 817481

Other (OTH) AF: 0.00 AC: 0 AN: 44222

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112887 Hom.: 0 Cov.: 24 AF XY: 0.0000285 AC XY: 1 AN XY: 35027

African (AFR) AF: 0.00 AC: 0 AN: 31149

American (AMR) AF: 0.00 AC: 0 AN: 10823

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2658

East Asian (EAS) AF: 0.00 AC: 0 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6265

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53224

Other (OTH) AF: 0.00 AC: 0 AN: 1526

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, X-linked 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	12
DANN	Benign	0.82
PhyloP100		1.1

Splicing

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

Other links and lift over

dbSNP: rs1411580863; hg19: chrX-53349623;