X-53320992-G-C

Variant names:

• chrX-53320992-G-C
• rs1556880287
• NM_001111125.3:c.132C>G

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.132C>G​(p.Ile44Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000956 in 1,046,153 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. Synonymous variant affecting the same amino acid position (i.e. I44I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.6e-7 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.176
• 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=0.19873437).

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.132C>G	p.Ile44Met	missense	Exon 1 of 15	NP_001104595.1
	IQSEC2	NM_001441092.1		c.132C>G	p.Ile44Met	missense	Exon 1 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.132C>G	p.Ile44Met	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.132C>G	p.Ile44Met	missense	Exon 1 of 15	ENSP00000495726.1
	IQSEC2	ENST00000706952.1		c.291C>G	p.Ile97Met	missense	Exon 1 of 15	ENSP00000516672.1
	IQSEC2	ENST00000674510.1		c.132C>G	p.Ile44Met	missense	Exon 1 of 15	ENSP00000502054.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.56e-7 AC: 1 AN: 1046153 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 341769

African (AFR) AF: 0.00 AC: 0 AN: 24888

American (AMR) AF: 0.00 AC: 0 AN: 27903

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18628

East Asian (EAS) AF: 0.00 AC: 0 AN: 27115

South Asian (SAS) AF: 0.00 AC: 0 AN: 49865

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30307

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4012

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 819135

Other (OTH) AF: 0.00 AC: 0 AN: 44300

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.18
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.40
MutPred		0.081		Gain of phosphorylation at T39 (P = 0.1878)
MVP		0.22
MPC		1.7
ClinPred		0.92	D
GERP RS		-0.63
PromoterAI		0.039	Neutral
Varity_R		0.41
gMVP		1.0
Mutation Taster		=89/11	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1556880287; hg19: chrX-53350190;