X-53251022-G-A

Variant names:

• chrX-53251022-G-A
• rs782768601
• NM_001111125.3:c.1554C>T

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.1554C>T​(p.Leu518Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 1,098,209 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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. L518L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 1 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0180
• 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.54).
• BP7: Synonymous conserved (PhyloP=-0.018 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.1554C>T	p.Leu518Leu	synonymous	Exon 5 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001441092.1		c.1554C>T	p.Leu518Leu	synonymous	Exon 5 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.1554C>T	p.Leu518Leu	synonymous	Exon 5 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.1554C>T	p.Leu518Leu	synonymous	Exon 5 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.939C>T	p.Leu313Leu	synonymous	Exon 5 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000706952.1		c.1713C>T	p.Leu571Leu	synonymous	Exon 5 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182838 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000182 AC: 2 AN: 1098209 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 1 AN XY: 363571

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19384

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000369 AC: 2 AN: 54148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 842116

Other (OTH) AF: 0.00 AC: 0 AN: 46095

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.6
DANN	Benign	0.73
PhyloP100		-0.018
PromoterAI		-0.027	Neutral

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

Other links and lift over

dbSNP: rs782768601; hg19: chrX-53280204;