rs1037744173

chrX-53320481-G-A

Variant summary

Our verdict is Likely benign. Variant got -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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 471276.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.643C>T	p.Pro215Ser	missense_variant	1/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.643C>T	p.Pro215Ser	missense_variant	1/15		NM_001111125.3	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000244

Gnomad4 OTH exome AF: 0.00

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Sep 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

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
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T;.;T
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Pathogenic	0.86	D
Vest4		0.28
MutPred		0.30		Gain of phosphorylation at P215 (P = 0.0041);Gain of phosphorylation at P215 (P = 0.0041);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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1037744173; hg19: chrX-53349679;