Variant rs369906117 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_001111125.3(IQSEC2):c.3452-22G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,156,199 control chromosomes in the GnomAD database, including 3 homozygotes. There are 547 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., 46 hem., cov: 23)

Exomes 𝑓: 0.0015 ( 3 hom. 501 hem. )

Consequence

IQSEC2
NM_001111125.3 intron

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.48

Variant links:

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 links:

IQSEC2 (HGNC:):

IQSEC2 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.31).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00149 (1556/1044593) while in subpopulation MID AF= 0.0104 (36/3476). AF 95% confidence interval is 0.00769. There are 3 homozygotes in gnomad4_exome. There are 501 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 46 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 linkuse as main transcript	c.3452-22G>A		intron_variant		ENST00000642864.1	NP_001104595.1	Q5JU85-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1 linkuse as main transcript	c.3452-22G>A		intron_variant			NM_001111125.3	ENSP00000495726.1		Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

159

AN:

111558

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

AN XY:

33738

show subpopulations

Gnomad AFR

AF:

0.000229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00160

Gnomad ASJ

AF:

0.00304

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000162

Gnomad MID

AF:

0.00424

Gnomad NFE

AF:

0.00232

Gnomad OTH

AF:

0.00132

GnomAD3 exomes

AF:

0.00142

AC:

152

AN:

106955

Hom.:

AF XY:

0.00132

AC XY:

AN XY:

35481

show subpopulations

Gnomad AFR exome

AF:

0.000159

Gnomad AMR exome

AF:

0.00151

Gnomad ASJ exome

AF:

0.00194

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000706

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00239

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00149

AC:

1556

AN:

1044593

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

501

AN XY:

336937

show subpopulations

Gnomad4 AFR exome

AF:

0.000726

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.00159

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000471

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.00164

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.00142

AC:

159

AN:

111606

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

AN XY:

33796

show subpopulations

Gnomad4 AFR

AF:

0.000229

Gnomad4 AMR

AF:

0.00160

Gnomad4 ASJ

AF:

0.00304

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000162

Gnomad4 NFE

AF:

0.00232

Gnomad4 OTH

AF:

0.00131

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.00160

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 23, 2015

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over