NM_001111125.3:c.294C>G

Variant names:

• chrX-53320830-G-C
• rs1556880235
• NM_001111125.3:c.294C>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001111125.3(IQSEC2):​c.294C>G​(p.His98Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000381 in 1,051,144 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. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H98H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000038 (0 hom. 2 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.458
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13130388).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001111125.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	NM_001111125.3	MANE Select	c.294C>G	p.His98Gln	missense	Exon 1 of 15	NP_001104595.1
	IQSEC2	NM_001441092.1		c.294C>G	p.His98Gln	missense	Exon 1 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.294C>G	p.His98Gln	missense	Exon 1 of 14	NP_001397665.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.294C>G	p.His98Gln	missense	Exon 1 of 15	ENSP00000495726.1
	IQSEC2	ENST00000706952.1		c.453C>G	p.His151Gln	missense	Exon 1 of 15	ENSP00000516672.1
	IQSEC2	ENST00000674510.1		c.294C>G	p.His98Gln	missense	Exon 1 of 15	ENSP00000502054.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000381 AC: 4 AN: 1051144 Hom.: 0 Cov.: 32 AF XY: 0.00000584 AC XY: 2 AN XY: 342584

African (AFR) AF: 0.00 AC: 0 AN: 24853

American (AMR) AF: 0.00 AC: 0 AN: 27809

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18544

East Asian (EAS) AF: 0.00 AC: 0 AN: 27044

South Asian (SAS) AF: 0.00 AC: 0 AN: 49672

European-Finnish (FIN) AF: 0.000107 AC: 4 AN: 37265

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4054

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 817683

Other (OTH) AF: 0.00 AC: 0 AN: 44220

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.015	T
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.46
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.091
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.26	T
Vest4		0.12
MutPred		0.080		Gain of MoRF binding (P = 0.103)
MVP		0.14
MPC		1.2
ClinPred		0.37	T
GERP RS		-0.028
PromoterAI		-0.067	Neutral
Varity_R		0.27
gMVP		0.70
Mutation Taster		=76/24	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1556880235; hg19: chrX-53350028;