rs369906117

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

0 publications found

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 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

IQSEC2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

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

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00142 (159/111606) while in subpopulation NFE AF = 0.00232 (123/52966). AF 95% confidence interval is 0.00199. There are 0 homozygotes in GnomAd4. There are 46 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. 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 rank	MANE	Protein	UniProt
IQSEC2	NM_001111125.3 link	c.3452-22G>A		intron_variant	Intron 13 of 14	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1 link	c.3452-22G>A		intron_variant	Intron 13 of 14		NM_001111125.3	ENSP00000495726.1

Frequencies

GnomAD3 genomes

AF:

0.00143

AC:

159

AN:

111558

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00142

AC:

152

AN:

106955

AF XY:

0.00132

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 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

African (AFR)

AF:

0.000726

AC:

AN:

24790

American (AMR)

AF:

0.00170

AC:

AN:

27663

Ashkenazi Jewish (ASJ)

AF:

0.00159

AC:

AN:

18270

East Asian (EAS)

AF:

0.00

AC:

AN:

27008

South Asian (SAS)

AF:

0.000471

AC:

AN:

48873

European-Finnish (FIN)

AF:

0.000187

AC:

AN:

37437

Middle Eastern (MID)

AF:

0.0104

AC:

AN:

3476

European-Non Finnish (NFE)

AF:

0.00164

AC:

1332

AN:

813153

Other (OTH)

AF:

0.00146

AC:

AN:

43923

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

142

190

237

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00142

AC:

159

AN:

111606

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

AN XY:

33796

show subpopulations

African (AFR)

AF:

0.000229

AC:

AN:

30582

American (AMR)

AF:

0.00160

AC:

AN:

10652

Ashkenazi Jewish (ASJ)

AF:

0.00304

AC:

AN:

2628

East Asian (EAS)

AF:

0.00

AC:

AN:

3514

South Asian (SAS)

AF:

0.00

AC:

AN:

2672

European-Finnish (FIN)

AF:

0.000162

AC:

AN:

6166

Middle Eastern (MID)

AF:

0.00465

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00232

AC:

123

AN:

52966

Other (OTH)

AF:

0.00131

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

Jun 23, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.88

PhyloP100

3.5

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over