X-53239256-C-T

Variant names:

• chrX-53239256-C-T
• rs782748833
• NM_001111125.3:c.3054G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001111125.3(IQSEC2):​c.3054G>A​(p.Thr1018Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000201 in 1,096,581 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T1018T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000020 (0 hom. 12 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -6.24
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant X-53239256-C-T is Benign according to our data. Variant chrX-53239256-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 523028.
• BP7: Synonymous conserved (PhyloP=-6.24 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome4 at 12 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.3054G>A	p.Thr1018Thr	synonymous	Exon 11 of 15	NP_001104595.1
	IQSEC2	NM_001441092.1		c.3054G>A	p.Thr1018Thr	synonymous	Exon 11 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.3054G>A	p.Thr1018Thr	synonymous	Exon 11 of 14	NP_001397665.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.3054G>A	p.Thr1018Thr	synonymous	Exon 11 of 15	ENSP00000495726.1
	IQSEC2	ENST00000375365.2	TSL:1	c.2439G>A	p.Thr813Thr	synonymous	Exon 11 of 14	ENSP00000364514.2
	IQSEC2	ENST00000706952.1		c.3213G>A	p.Thr1071Thr	synonymous	Exon 11 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183229 AF XY: 0.0000591

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: 0.0000201 AC: 22 AN: 1096581 Hom.: 0 Cov.: 29 AF XY: 0.0000332 AC XY: 12 AN XY: 361981

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

American (AMR) AF: 0.00 AC: 0 AN: 35195

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19371

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

South Asian (SAS) AF: 0.000296 AC: 16 AN: 54103

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40430

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4085

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840820

Other (OTH) AF: 0.0000217 AC: 1 AN: 46020

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Intellectual disability, X-linked 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	1.7
DANN	Benign	0.72
PhyloP100		-6.2
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs782748833; hg19: chrX-53268438; COSMIC: COSV64726114; COSMIC: COSV64726114;