X-53320528-G-C

Position:

• chrX-53320528-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001111125.3(IQSEC2):​c.596C>G​(p.Pro199Arg) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 24)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.740

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17293856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.596C>G	p.Pro199Arg	missense_variant	1/15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.596C>G	p.Pro199Arg	missense_variant	1/15		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	.;T;T
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.79	T;.;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.3	.;N;.
REVEL	Benign	0.066
Sift	Benign	0.094	.;T;.
Sift4G	Uncertain	0.012	.;D;.
Vest4		0.19
MutPred		0.29		Loss of glycosylation at P199 (P = 0.0143);Loss of glycosylation at P199 (P = 0.0143);Loss of glycosylation at P199 (P = 0.0143);
MVP		0.51
MPC		1.3
ClinPred		0.51	D
GERP RS		3.1
Varity_R		0.18
gMVP		0.19

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs782439813; hg19: chrX-53349726;