X-53320440-G-T

Variant names:

• chrX-53320440-G-T
• rs781940286
• NM_001111125.3:c.684C>A

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.684C>A​(p.Ser228Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000951 in 1,051,944 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes 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. S228S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.5e-7 (0 hom. 1 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.20
• 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=0.17292494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.684C>A	p.Ser228Arg	missense_variant	Exon 1 of 15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.684C>A	p.Ser228Arg	missense_variant	Exon 1 of 15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.51e-7 AC: 1 AN: 1051944 Hom.: 0 Cov.: 31 AF XY: 0.00000291 AC XY: 1 AN XY: 343242

African (AFR) AF: 0.00 AC: 0 AN: 24779

American (AMR) AF: 0.00 AC: 0 AN: 27882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18594

East Asian (EAS) AF: 0.00 AC: 0 AN: 27024

South Asian (SAS) AF: 0.00 AC: 0 AN: 49813

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3610

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 818453

Other (OTH) AF: 0.00 AC: 0 AN: 44247

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0	.;T;T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.80	T;.;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	.;N;N
PhyloP100		1.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.0	.;N;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;D;.
Sift4G	Pathogenic	0.0	.;T;.
Vest4		0.0
ClinPred		0.31	T
GERP RS		1.9
Varity_R		0.33
gMVP		0.34
Mutation Taster		=92/8	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs781940286; hg19: chrX-53349638;