rs781808414

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_001111125.3(IQSEC2):c.2831A>G(p.Asn944Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000206 in 1,165,804 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N944N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000021 ( 0 hom. 5 hem. )

Consequence

IQSEC2
NM_001111125.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 5.08

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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26932284).

BP6

Variant X-53243390-T-C is Benign according to our data. Variant chrX-53243390-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 471269.

BS2

High Hemizygotes in GnomAdExome4 at 5 XL gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IQSEC2	NM_001111125.3	MANE Select	c.2831A>G	p.Asn944Ser	missense	Exon 9 of 15	NP_001104595.1
IQSEC2	NM_001441092.1		c.2831A>G	p.Asn944Ser	missense	Exon 9 of 14	NP_001428021.1
IQSEC2	NM_001410736.1		c.2831A>G	p.Asn944Ser	missense	Exon 9 of 14	NP_001397665.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IQSEC2	ENST00000642864.1	MANE Select	c.2831A>G	p.Asn944Ser	missense	Exon 9 of 15	ENSP00000495726.1
IQSEC2	ENST00000375365.2	TSL:1	c.2216A>G	p.Asn739Ser	missense	Exon 9 of 14	ENSP00000364514.2
IQSEC2	ENST00000706952.1		c.2990A>G	p.Asn997Ser	missense	Exon 9 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes

AF:

0.0000181

AC:

AN:

110574

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000956

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000189

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000772

AC:

AN:

116509

AF XY:

0.0000738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000359

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000439

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000208

AC:

AN:

1055230

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

345126

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24992

American (AMR)

AF:

0.000321

AC:

AN:

28062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18640

East Asian (EAS)

AF:

0.00

AC:

AN:

27242

South Asian (SAS)

AF:

0.00

AC:

AN:

49912

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37726

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4088

European-Non Finnish (NFE)

AF:

0.0000122

AC:

AN:

820117

Other (OTH)

AF:

0.0000675

AC:

AN:

44451

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.0000181

AC:

AN:

110574

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32810

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30235

American (AMR)

AF:

0.0000956

AC:

AN:

10459

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2633

East Asian (EAS)

AF:

0.00

AC:

AN:

3526

South Asian (SAS)

AF:

0.00

AC:

AN:

2513

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6013

Middle Eastern (MID)

AF:

0.00

AC:

AN:

235

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

52808

Other (OTH)

AF:

0.00

AC:

AN:

1473

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Intellectual disability, X-linked 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.79

CADD

Benign

(source)

DANN

Uncertain

1.0

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.012

MetaRNN

Benign

0.27

MetaSVM

Benign

-1.1

PhyloP100

5.1

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.7

REVEL

Benign

0.085

Sift

Benign

0.034

Sift4G

Uncertain

0.048

Polyphen

0.0050

Vest4

0.25

MVP

0.71

MPC

0.88

ClinPred

0.41

GERP RS

5.3

Varity_R

0.78

gMVP

0.77

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over