rs782697291

Variant names:

• chrX-53236409-G-A
• rs782697291
• NM_001111125.3:c.3364C>T
• IQSEC2 p.Arg1122Cys

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001111125.3(IQSEC2):​c.3364C>T​(p.Arg1122Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000253 in 1,203,945 control chromosomes in the GnomAD database, including 2 homozygotes. There are 173 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1122H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., 5 hem., cov: 24)
  • Exomes 𝑓: 0.00027 (2 hom. 168 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:4
• Conservation: PhyloP100: 2.15
• Publications: 7 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010379791).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000106 (12/112914) while in subpopulation SAS AF = 0.00289 (8/2769). AF 95% confidence interval is 0.00144. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 5 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.3364C>T	p.Arg1122Cys	missense	Exon 13 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001441092.1		c.3364C>T	p.Arg1122Cys	missense	Exon 13 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.3364C>T	p.Arg1122Cys	missense	Exon 13 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.3364C>T	p.Arg1122Cys	missense	Exon 13 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.2749C>T	p.Arg917Cys	missense	Exon 13 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000706952.1		c.3523C>T	p.Arg1175Cys	missense	Exon 13 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes AF: 0.000106 AC: 12 AN: 112863 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00288

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000403 AC: 67 AN: 166346 AF XY: 0.000739

Gnomad AFR exome AF: 0.0000844

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: 0.0000413

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000269 AC: 293 AN: 1091031 Hom.: 2 Cov.: 32 AF XY: 0.000470 AC XY: 168 AN XY: 357533

African (AFR) AF: 0.00 AC: 0 AN: 26266

American (AMR) AF: 0.0000289 AC: 1 AN: 34590

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19233

East Asian (EAS) AF: 0.00 AC: 0 AN: 29920

South Asian (SAS) AF: 0.00364 AC: 192 AN: 52692

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39979

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4125

European-Non Finnish (NFE) AF: 0.000104 AC: 87 AN: 838406

Other (OTH) AF: 0.000262 AC: 12 AN: 45820

GnomAD4 genome AF: 0.000106 AC: 12 AN: 112914 Hom.: 0 Cov.: 24 AF XY: 0.000143 AC XY: 5 AN XY: 35080

African (AFR) AF: 0.0000641 AC: 2 AN: 31177

American (AMR) AF: 0.00 AC: 0 AN: 10818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3563

South Asian (SAS) AF: 0.00289 AC: 8 AN: 2769

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6267

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53210

Other (OTH) AF: 0.00 AC: 0 AN: 1549

Alfa AF: 0.000174 Hom.: 2

Bravo AF: 0.0000264

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	Abnormal brain morphology (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, X-linked 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	27
DANN	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.42	T
PhyloP100		2.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Benign	0.26
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.35
gMVP		0.78
Mutation Taster		=80/20	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs782697291;

hg19: chrX-53265591;