NM_001111125.3:c.803C>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001111125.3(IQSEC2):​c.803C>T​(p.Pro268Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000929 in 1,076,141 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P268R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.68
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: Ambry Genetics
• intellectual disability, X-linked 1

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• severe intellectual disability-progressive postnatal microcephaly- midline stereotypic hand movements syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2615186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.803C>T	p.Pro268Leu	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>T	p.Pro268Leu	missense_variant	Exon 3 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.29e-7 AC: 1 AN: 1076141 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 346813

African (AFR) AF: 0.0000385 AC: 1 AN: 25958

American (AMR) AF: 0.00 AC: 0 AN: 32636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18737

East Asian (EAS) AF: 0.00 AC: 0 AN: 29363

South Asian (SAS) AF: 0.00 AC: 0 AN: 51369

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39293

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 829570

Other (OTH) AF: 0.00 AC: 0 AN: 45231

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	24
DANN	Benign	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.74	T
PhyloP100		2.7
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	.;D;.;D;.
REVEL	Uncertain	0.36
Sift	Benign	0.10	.;T;.;T;.
Sift4G	Benign	0.86	.;T;.;T;.
Polyphen		0.023	.;.;.;B;.
Vest4		0.14, 0.11
MutPred		0.17		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		0.78
MPC		1.1
ClinPred		0.33	T
GERP RS		5.1
Varity_R		0.25
gMVP		0.46
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs368559547; hg19: chrX-53285178;