X-53234268-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001111125.3(IQSEC2):c.4418C>T(p.Pro1473Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 975,899 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 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). Synonymous variant affecting the same amino acid position (i.e. P1473P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 15)
  • Exomes 𝑓: 0.0000041 (0 hom. 2 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.93

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19100425).
• BP6: Variant X-53234268-G-A is Benign according to our data. Variant chrX-53234268-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1218277.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.4418C>T	p.Pro1473Leu	missense_variant	15/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.4418C>T	p.Pro1473Leu	missense_variant	15/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes Cov.: 15

GnomAD3 exomes AF: 0.0000166 AC: 1 AN: 60405 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 10167

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: 0.00

Gnomad NFE exome AF: 0.0000480

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 4 AN: 975899 Hom.: 0 Cov.: 21 AF XY: 0.00000678 AC XY: 2 AN XY: 294809

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: 0.00

Gnomad4 NFE exome AF: 0.00000516

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 15

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	IQSEC2: PM2, PP2 -

Intellectual disability, X-linked 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
Cadd	Uncertain	24
Dann	Uncertain	0.99
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.84	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.10
Sift	Uncertain	0.0010	D;.
Sift4G	Benign	0.16	T;.
Vest4		0.16
MutPred		0.27		Loss of glycosylation at P1473 (P = 0.025);Loss of glycosylation at P1473 (P = 0.025);
MVP		0.22
MPC		1.1
ClinPred		0.33	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.13

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: rs1556858927; hg19: chrX-53263450;