chrX-53320481-G-A

Variant names:

• chrX-53320481-G-A
• rs1037744173
• NM_001111125.3:c.643C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001111125.3(IQSEC2):​c.643C>T​(p.Pro215Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. P215P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000019 (0 hom. 2 hem.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.13
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19054875).
• BP6: Variant X-53320481-G-A is Benign according to our data. Variant chrX-53320481-G-A is described in ClinVar as Benign. ClinVar VariationId is 471276.Status of the report is criteria_provided_single_submitter, 1 stars.

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.643C>T	p.Pro215Ser	missense	Exon 1 of 15	NP_001104595.1
	IQSEC2	NM_001441092.1		c.643C>T	p.Pro215Ser	missense	Exon 1 of 14	NP_001428021.1
	IQSEC2	NM_001410736.1		c.643C>T	p.Pro215Ser	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.643C>T	p.Pro215Ser	missense	Exon 1 of 15	ENSP00000495726.1
	IQSEC2	ENST00000706952.1		c.802C>T	p.Pro268Ser	missense	Exon 1 of 15	ENSP00000516672.1
	IQSEC2	ENST00000674510.1		c.643C>T	p.Pro215Ser	missense	Exon 1 of 15	ENSP00000502054.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000190 AC: 2 AN: 1051416 Hom.: 0 Cov.: 31 AF XY: 0.00000583 AC XY: 2 AN XY: 343300

African (AFR) AF: 0.00 AC: 0 AN: 24670

American (AMR) AF: 0.00 AC: 0 AN: 27845

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18579

East Asian (EAS) AF: 0.00 AC: 0 AN: 26931

South Asian (SAS) AF: 0.00 AC: 0 AN: 49759

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37313

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3245

European-Non Finnish (NFE) AF: 0.00000244 AC: 2 AN: 818856

Other (OTH) AF: 0.00 AC: 0 AN: 44218

GnomAD4 genome Cov.: 23

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 1 Benign:1

Sep 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.1
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.072
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.074	T
Vest4		0.28
MutPred		0.30		Gain of phosphorylation at P215 (P = 0.0041)
MVP		0.28
MPC		1.1
ClinPred		0.44	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.34
Mutation Taster		=96/4	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1037744173; hg19: chrX-53349679;