rs185512321

Positions:

• chrX-53320647-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001111125.3(IQSEC2):​c.477G>A​(p.Leu159=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00387 in 1,162,443 control chromosomes in the GnomAD database, including 105 homozygotes. There are 1,276 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (50 hom., 671 hem., cov: 23)
  • Exomes 𝑓: 0.0021 (55 hom. 605 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.505

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant X-53320647-C-T is Benign according to our data. Variant chrX-53320647-C-T is described in ClinVar as [Benign]. Clinvar id is 93558.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-53320647-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.505 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0693 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.477G>A	p.Leu159=	synonymous_variant	1/15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.477G>A	p.Leu159=	synonymous_variant	1/15		NM_001111125.3	ENSP00000495726	P1

Frequencies

GnomAD3 genomes AF: 0.0207 AC: 2324 AN: 112334 Hom.: 50 Cov.: 23 AF XY: 0.0193 AC XY: 667 AN XY: 34590

Gnomad AFR AF: 0.0718

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00646

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00110

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000942

Gnomad OTH AF: 0.0171

GnomAD3 exomes AF: 0.00459 AC: 476 AN: 103729 Hom.: 13 AF XY: 0.00331 AC XY: 119 AN XY: 35987

Gnomad AFR exome AF: 0.0742

Gnomad AMR exome AF: 0.00305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000146

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000267

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.00207 AC: 2172 AN: 1050058 Hom.: 55 Cov.: 32 AF XY: 0.00177 AC XY: 605 AN XY: 342216

Gnomad4 AFR exome AF: 0.0747

Gnomad4 AMR exome AF: 0.00390

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000367

Gnomad4 OTH exome AF: 0.00407

GnomAD4 genome AF: 0.0207 AC: 2329 AN: 112385 Hom.: 50 Cov.: 23 AF XY: 0.0194 AC XY: 671 AN XY: 34651

Gnomad4 AFR AF: 0.0718

Gnomad4 AMR AF: 0.00646

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00110

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000943

Gnomad4 OTH AF: 0.0169

Alfa AF: 0.0108 Hom.: 52

Bravo AF: 0.0230

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 25, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Intellectual disability, X-linked 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	15
DANN	Benign	0.96

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs185512321; hg19: chrX-53349845;