NM_001111125.3:c.1592G>C

Variant names:

• chrX-53250984-C-G
• rs149027201
• NM_001111125.3:c.1592G>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.1592G>C​(p.Arg531Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000303 in 1,210,403 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 113 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. R531Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., 14 hem., cov: 23)
  • Exomes 𝑓: 0.00030 (0 hom. 99 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.85
• Publications: 1 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=0.015024185).
• BP6: Variant X-53250984-C-G is Benign according to our data. Variant chrX-53250984-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 14 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.1592G>C	p.Arg531Pro	missense	Exon 5 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001441092.1		c.1592G>C	p.Arg531Pro	missense	Exon 5 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.1592G>C	p.Arg531Pro	missense	Exon 5 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.1592G>C	p.Arg531Pro	missense	Exon 5 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000375365.2	TSL:1	c.977G>C	p.Arg326Pro	missense	Exon 5 of 14	ENSP00000364514.2	Q5JU85-3
	IQSEC2	ENST00000706952.1		c.1751G>C	p.Arg584Pro	missense	Exon 5 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 34 AN: 112170 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000937

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00195

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000357

Gnomad OTH AF: 0.000664

GnomAD2 exomes AF: 0.000401 AC: 73 AN: 182224 AF XY: 0.000328

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: 0.00181

Gnomad NFE exome AF: 0.000544

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000303 AC: 333 AN: 1098180 Hom.: 0 Cov.: 33 AF XY: 0.000272 AC XY: 99 AN XY: 363546

African (AFR) AF: 0.00 AC: 0 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19380

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.00 AC: 0 AN: 54147

European-Finnish (FIN) AF: 0.00163 AC: 66 AN: 40506

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.000308 AC: 259 AN: 842103

Other (OTH) AF: 0.000174 AC: 8 AN: 46095

GnomAD4 genome AF: 0.000303 AC: 34 AN: 112223 Hom.: 0 Cov.: 23 AF XY: 0.000407 AC XY: 14 AN XY: 34397

African (AFR) AF: 0.0000323 AC: 1 AN: 30917

American (AMR) AF: 0.0000936 AC: 1 AN: 10682

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3534

South Asian (SAS) AF: 0.00 AC: 0 AN: 2711

European-Finnish (FIN) AF: 0.00195 AC: 12 AN: 6139

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000357 AC: 19 AN: 53163

Other (OTH) AF: 0.000657 AC: 1 AN: 1523

Alfa AF: 0.000118 Hom.: 2

Bravo AF: 0.000178

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000297 AC: 2

ExAC AF: 0.000469 AC: 57

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Intellectual disability, X-linked 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.15
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.075	T
Polyphen		0.011	B
Vest4		0.51
MVP		0.60
MPC		2.6
ClinPred		0.077	T
GERP RS		4.4
PromoterAI		-0.0066	Neutral
Varity_R		0.42
gMVP		0.68
Mutation Taster		=74/26	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: rs149027201; hg19: chrX-53280166;