rs782051125

Variant names:

• chrX-53320936-T-C
• rs782051125
• NM_001111125.3:c.188A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001111125.3(IQSEC2):​c.188A>G​(p.Glu63Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000125 in 1,160,224 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 38 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E63K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., 6 hem., cov: 22)
  • Exomes 𝑓: 0.00010 (0 hom. 32 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 1.43
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005777359).
• BP6: Variant X-53320936-T-C is Benign according to our data. Variant chrX-53320936-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 383983.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000317 (35/110294) while in subpopulation EAS AF = 0.00322 (11/3412). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 6 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.188A>G	p.Glu63Gly	missense	Exon 1 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001441092.1		c.188A>G	p.Glu63Gly	missense	Exon 1 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.188A>G	p.Glu63Gly	missense	Exon 1 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.188A>G	p.Glu63Gly	missense	Exon 1 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000706952.1		c.347A>G	p.Glu116Gly	missense	Exon 1 of 15	ENSP00000516672.1	A0A9L9PY69
	IQSEC2	ENST00000674510.1		c.188A>G	p.Glu63Gly	missense	Exon 1 of 15	ENSP00000502054.1	Q5JU85-2

Frequencies

GnomAD3 genomes AF: 0.000317 AC: 35 AN: 110239 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00207

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00321

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.000297 AC: 31 AN: 104244 AF XY: 0.000272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000516

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00377

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 110 AN: 1049930 Hom.: 0 Cov.: 31 AF XY: 0.0000933 AC XY: 32 AN XY: 342862

African (AFR) AF: 0.00 AC: 0 AN: 24898

American (AMR) AF: 0.0000358 AC: 1 AN: 27904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18628

East Asian (EAS) AF: 0.00302 AC: 82 AN: 27123

South Asian (SAS) AF: 0.00 AC: 0 AN: 49870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33737

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3978

European-Non Finnish (NFE) AF: 0.00000366 AC: 3 AN: 819467

Other (OTH) AF: 0.000541 AC: 24 AN: 44325

GnomAD4 genome AF: 0.000317 AC: 35 AN: 110294 Hom.: 0 Cov.: 22 AF XY: 0.000183 AC XY: 6 AN XY: 32734

African (AFR) AF: 0.00 AC: 0 AN: 30367

American (AMR) AF: 0.00207 AC: 22 AN: 10617

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00322 AC: 11 AN: 3412

South Asian (SAS) AF: 0.00 AC: 0 AN: 2471

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6043

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52366

Other (OTH) AF: 0.00133 AC: 2 AN: 1509

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000125

ExAC AF: 0.000217 AC: 5

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, X-linked 1 (2)
-	-	1	IQSEC2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.017	T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Vest4		0.17
MutPred		0.049		Gain of MoRF binding (P = 0.0652)
MVP		0.28
MPC		1.3
ClinPred		0.051	T
GERP RS		2.7
PromoterAI		-0.011	Neutral
Varity_R		0.17
gMVP		0.84
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs782051125; hg19: chrX-53350134;