rs782357394

Variant names:

• chrX-53320546-C-G
• rs782357394
• NM_001111125.3:c.578G>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001111125.3(IQSEC2):​c.578G>C​(p.Gly193Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000513 in 1,154,368 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 169 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G193G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 6 hem., cov: 24)
  • Exomes 𝑓: 0.00054 (0 hom. 163 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.01
• 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06268445).
• BP6: Variant X-53320546-C-G is Benign according to our data. Variant chrX-53320546-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 379876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.578G>C	p.Gly193Ala	missense	Exon 1 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001441092.1		c.578G>C	p.Gly193Ala	missense	Exon 1 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.578G>C	p.Gly193Ala	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.578G>C	p.Gly193Ala	missense	Exon 1 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000706952.1		c.737G>C	p.Gly246Ala	missense	Exon 1 of 15	ENSP00000516672.1	A0A9L9PY69
	IQSEC2	ENST00000674510.1		c.578G>C	p.Gly193Ala	missense	Exon 1 of 15	ENSP00000502054.1	Q5JU85-2

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 31 AN: 112458 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000927

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: 0.000509

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000368 AC: 34 AN: 92344 AF XY: 0.000398

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: 0.0000887

Gnomad NFE exome AF: 0.000991

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000538 AC: 561 AN: 1041865 Hom.: 0 Cov.: 31 AF XY: 0.000483 AC XY: 163 AN XY: 337679

African (AFR) AF: 0.0000425 AC: 1 AN: 23534

American (AMR) AF: 0.0000369 AC: 1 AN: 27108

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18083

East Asian (EAS) AF: 0.00 AC: 0 AN: 25962

South Asian (SAS) AF: 0.00 AC: 0 AN: 48882

European-Finnish (FIN) AF: 0.0000272 AC: 1 AN: 36760

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2955

European-Non Finnish (NFE) AF: 0.000673 AC: 548 AN: 814772

Other (OTH) AF: 0.000228 AC: 10 AN: 43809

GnomAD4 genome AF: 0.000276 AC: 31 AN: 112503 Hom.: 0 Cov.: 24 AF XY: 0.000173 AC XY: 6 AN XY: 34755

African (AFR) AF: 0.0000963 AC: 3 AN: 31147

American (AMR) AF: 0.0000926 AC: 1 AN: 10802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3514

South Asian (SAS) AF: 0.00 AC: 0 AN: 2757

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.000509 AC: 27 AN: 53000

Other (OTH) AF: 0.00 AC: 0 AN: 1548

Alfa AF: 0.000174 Hom.: 1

Bravo AF: 0.000212

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	21
DANN	Benign	0.96
DEOGEN2	Benign	0.013	T
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.063	D
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.070
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.31	T
Vest4		0.18
MVP		0.25
MPC		1.2
ClinPred		0.14	T
GERP RS		3.0
Varity_R		0.17
gMVP		0.41
Mutation Taster		=91/9	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs782357394; hg19: chrX-53349744;