X-53250935-C-T

Position:

• chrX-53250935-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001111125.3(IQSEC2):​c.1641G>A​(p.Ala547=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00389 in 1,199,171 control chromosomes in the GnomAD database, including 108 homozygotes. There are 1,213 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (56 hom., 603 hem., cov: 23)
  • Exomes 𝑓: 0.0022 (52 hom. 610 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.929

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant X-53250935-C-T is Benign according to our data. Variant chrX-53250935-C-T is described in ClinVar as [Benign]. Clinvar id is 129280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.929 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.1641G>A	p.Ala547=	synonymous_variant	5/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.1641G>A	p.Ala547=	synonymous_variant	5/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 2273 AN: 112455 Hom.: 56 Cov.: 23 AF XY: 0.0173 AC XY: 600 AN XY: 34671

Gnomad AFR AF: 0.0698

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00754

Gnomad ASJ AF: 0.000756

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000731

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000169

Gnomad OTH AF: 0.0126

GnomAD3 exomes AF: 0.00641 AC: 1041 AN: 162299 Hom.: 18 AF XY: 0.00386 AC XY: 217 AN XY: 56191

Gnomad AFR exome AF: 0.0780

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.00106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000119

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000270

Gnomad OTH exome AF: 0.00318

GnomAD4 exome AF: 0.00221 AC: 2400 AN: 1086666 Hom.: 52 Cov.: 33 AF XY: 0.00171 AC XY: 610 AN XY: 356188

Gnomad4 AFR exome AF: 0.0699

Gnomad4 AMR exome AF: 0.00538

Gnomad4 ASJ exome AF: 0.000583

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00540

GnomAD4 genome AF: 0.0202 AC: 2270 AN: 112505 Hom.: 56 Cov.: 23 AF XY: 0.0174 AC XY: 603 AN XY: 34731

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.00744

Gnomad4 ASJ AF: 0.000756

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000733

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000169

Gnomad4 OTH AF: 0.0124

Alfa AF: 0.0131 Hom.: 73

Bravo AF: 0.0240

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 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. -

Intellectual disability, X-linked 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	2.4
DANN	Benign	0.80

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: rs61745228; hg19: chrX-53280117;