chrX-53255996-G-C

Variant names:

• chrX-53255996-G-C
• rs368559547
• NM_001111125.3:c.803C>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_001111125.3(IQSEC2):​c.803C>G​(p.Pro268Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000444 in 112,618 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.68

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24374515).
• BP6: Variant X-53255996-G-C is Benign according to our data. Variant chrX-53255996-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1442992.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.803C>G	p.Pro268Arg	missense_variant	Exon 3 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.803C>G	p.Pro268Arg	missense_variant	Exon 3 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes AF: 0.0000444 AC: 5 AN: 112618 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34776

Gnomad AFR AF: 0.000161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000704 AC: 1 AN: 142023 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 40759

Gnomad AFR exome AF: 0.000104

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000186 AC: 2 AN: 1076141 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 346813

Gnomad4 AFR exome AF: 0.0000770

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000444 AC: 5 AN: 112618 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34776

Gnomad4 AFR AF: 0.000161

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jan 16, 2018

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P268R variant (also known as c.803C>G), located in coding exon 3 of the IQSEC2 gene, results from a C to G substitution at nucleotide position 803. The proline at codon 268 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Intellectual disability, X-linked 1 Benign:1

Apr 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.0017	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;.;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-0.51	T
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.1	.;N;.;N;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.0040	.;D;.;T;.
Sift4G	Benign	0.61	.;T;.;T;.
Polyphen		0.98	.;.;.;D;.
Vest4		0.15, 0.14
MutPred		0.15		Loss of glycosylation at P268 (P = 0.0127);Loss of glycosylation at P268 (P = 0.0127);Loss of glycosylation at P268 (P = 0.0127);.;.;
MVP		0.82
MPC		1.5
ClinPred		0.28	T
GERP RS		5.1
Varity_R		0.34
gMVP		0.49

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: rs368559547; hg19: chrX-53285178;