rs781830206

Positions:

• chrX-53250523-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001111125.3(IQSEC2):​c.2053G>A​(p.Glu685Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000182 in 1,210,458 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 4 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.58

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07511562).
• BP6: Variant X-53250523-C-T is Benign according to our data. Variant chrX-53250523-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 471266.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS2: High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.2053G>A	p.Glu685Lys	missense_variant	5/15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.2053G>A	p.Glu685Lys	missense_variant	5/15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes AF: 0.0000445 AC: 5 AN: 112378 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34522

Gnomad AFR AF: 0.0000323

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000561

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000376

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000328 AC: 6 AN: 182656 Hom.: 0 AF XY: 0.0000298 AC XY: 2 AN XY: 67220

Gnomad AFR exome AF: 0.0000761

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000289

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1098026 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 4 AN XY: 363398

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000445 AC: 5 AN: 112432 Hom.: 0 Cov.: 23 AF XY: 0.0000289 AC XY: 1 AN XY: 34586

Gnomad4 AFR AF: 0.0000322

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000563

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000376

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, X-linked 1 Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Oct 11, 2018	BP5; This variant was found in a case with an alternate molecular basis of disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	22
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;.;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.075	T;T;T;T
MetaSVM	Benign	-0.99	T
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.6	.;N;.;N
REVEL	Benign	0.024
Sift	Uncertain	0.028	.;D;.;T
Sift4G	Benign	0.14	.;T;.;T
Polyphen		0.038	.;.;.;B
Vest4		0.37, 0.31
MutPred		0.25		Gain of methylation at E685 (P = 0.0064);Gain of methylation at E685 (P = 0.0064);Gain of methylation at E685 (P = 0.0064);.;
MVP		0.37
MPC		1.2
ClinPred		0.089	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.48

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: rs781830206; hg19: chrX-53279705;