rs149027201

chrX-53250984-C-GchrX-53250984-C-T

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 435521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.1592G>C	p.Arg531Pro	missense_variant	5/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.1592G>C	p.Arg531Pro	missense_variant	5/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 34 AN: 112170 Hom.: 0 Cov.: 23 AF XY: 0.000408 AC XY: 14 AN XY: 34332

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

GnomAD3 exomes AF: 0.000401 AC: 73 AN: 182224 Hom.: 0 AF XY: 0.000328 AC XY: 22 AN XY: 67106

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 SAS 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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.000308

Gnomad4 OTH exome AF: 0.000174

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

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.0000936

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00195

Gnomad4 NFE AF: 0.000357

Gnomad4 OTH AF: 0.000657

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

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	IQSEC2: PP2, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 25, 2016

- -

Intellectual disability, X-linked 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

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;.;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.015	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
Polyphen		0.011	.;.;.;B
Vest4		0.51, 0.51
MVP		0.60
MPC		2.6
ClinPred		0.077	T
GERP RS		4.4
Varity_R		0.42
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs149027201; hg19: chrX-53280166;