rs781862515

Variant names:

• chrX-53239229-G-A
• rs781862515
• NM_001111125.3:c.3081C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_001111125.3(IQSEC2):​c.3081C>T​(p.Leu1027Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,208,207 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. L1027L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000012 (0 hom. 4 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.572
• 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), Ambry Genetics, G2P
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant X-53239229-G-A is Benign according to our data. Variant chrX-53239229-G-A is described in ClinVar as Benign. ClinVar VariationId is 538611.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.572 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

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.3081C>T	p.Leu1027Leu	synonymous	Exon 11 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001441092.1		c.3081C>T	p.Leu1027Leu	synonymous	Exon 11 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.3081C>T	p.Leu1027Leu	synonymous	Exon 11 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.3081C>T	p.Leu1027Leu	synonymous	Exon 11 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.2466C>T	p.Leu822Leu	synonymous	Exon 11 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000706952.1		c.3240C>T	p.Leu1080Leu	synonymous	Exon 11 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 111987 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000325

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183275 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000146

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: 0.0000119 AC: 13 AN: 1096220 Hom.: 0 Cov.: 28 AF XY: 0.0000111 AC XY: 4 AN XY: 361648

African (AFR) AF: 0.00 AC: 0 AN: 26365

American (AMR) AF: 0.000142 AC: 5 AN: 35201

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54093

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4107

European-Non Finnish (NFE) AF: 0.00000714 AC: 6 AN: 840409

Other (OTH) AF: 0.0000217 AC: 1 AN: 46027

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 111987 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34163

African (AFR) AF: 0.0000325 AC: 1 AN: 30798

American (AMR) AF: 0.00 AC: 0 AN: 10603

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2689

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6106

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53173

Other (OTH) AF: 0.00 AC: 0 AN: 1504

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: 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	-0.36
CADD	Benign	6.2
DANN	Benign	0.73
PhyloP100		-0.57
Mutation Taster		=97/3	polymorphism

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: rs781862515; hg19: chrX-53268411;