chrX-53320732-C-G

Variant names:

• chrX-53320732-C-G
• rs1556880174
• NM_001111125.3:c.392G>C

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.392G>C​(p.Arg131Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000664 in 1,053,503 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000066 (0 hom. 2 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0310
• 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), Ambry Genetics, G2P
• 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=0.14843887).
• 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	NM_001111125.3	MANE Select	c.392G>C	p.Arg131Pro	missense	Exon 1 of 15	NP_001104595.1	Q5JU85-2
	IQSEC2	NM_001441092.1		c.392G>C	p.Arg131Pro	missense	Exon 1 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.392G>C	p.Arg131Pro	missense	Exon 1 of 14	NP_001397665.1	A0A1W2PR28

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.392G>C	p.Arg131Pro	missense	Exon 1 of 15	ENSP00000495726.1	Q5JU85-2
	IQSEC2	ENST00000706952.1		c.551G>C	p.Arg184Pro	missense	Exon 1 of 15	ENSP00000516672.1	A0A9L9PY69
	IQSEC2	ENST00000674510.1		c.392G>C	p.Arg131Pro	missense	Exon 1 of 15	ENSP00000502054.1	Q5JU85-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000925 AC: 1 AN: 108142 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000253

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000664 AC: 7 AN: 1053503 Hom.: 0 Cov.: 32 AF XY: 0.00000580 AC XY: 2 AN XY: 344619

African (AFR) AF: 0.00 AC: 0 AN: 24900

American (AMR) AF: 0.00 AC: 0 AN: 27905

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18633

East Asian (EAS) AF: 0.0000369 AC: 1 AN: 27129

South Asian (SAS) AF: 0.00 AC: 0 AN: 49875

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4004

European-Non Finnish (NFE) AF: 0.00000732 AC: 6 AN: 819446

Other (OTH) AF: 0.00 AC: 0 AN: 44355

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, X-linked 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.031
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	0.21	N
REVEL	Benign	0.086
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.34	T
Vest4		0.31
MutPred		0.28		Loss of MoRF binding (P = 0.0603)
MVP		0.30
MPC		1.8
ClinPred		0.38	T
GERP RS		3.0
Varity_R		0.35
gMVP		0.67
Mutation Taster		=82/18	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1556880174; hg19: chrX-53349930;