dbSNP rs782713602: IQSEC2:p.Asn28Asn (chrX-53321040-G-A) – ACMG Classification: Benign (-17 pts)

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_001111125.3(IQSEC2):c.84C>T(p.Asn28Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000619 in 1,153,018 control chromosomes in the GnomAD database, including 7 homozygotes. There are 239 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., 66 hem., cov: 21)

Exomes 𝑓: 0.00057 ( 7 hom. 173 hem. )

Consequence

IQSEC2
NM_001111125.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.31

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
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 -17 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant X-53321040-G-A is Benign according to our data. Variant chrX-53321040-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382662.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.31 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 66 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	UniProt
IQSEC2	NM_001111125.3	MANE Select	c.84C>T	p.Asn28Asn	synonymous	Exon 1 of 15	NP_001104595.1	Q5JU85-2
IQSEC2	NM_001441092.1		c.84C>T	p.Asn28Asn	synonymous	Exon 1 of 14	NP_001428021.1
IQSEC2	NM_001410736.1		c.84C>T	p.Asn28Asn	synonymous	Exon 1 of 14	NP_001397665.1	A0A1W2PR28

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQSEC2	ENST00000642864.1	MANE Select	c.84C>T	p.Asn28Asn	synonymous	Exon 1 of 15	ENSP00000495726.1	Q5JU85-2
IQSEC2	ENST00000706952.1		c.243C>T	p.Asn81Asn	synonymous	Exon 1 of 15	ENSP00000516672.1	A0A9L9PY69
IQSEC2	ENST00000674510.1		c.84C>T	p.Asn28Asn	synonymous	Exon 1 of 15	ENSP00000502054.1	Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

120

AN:

109422

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000294

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0173

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000307

Gnomad OTH

AF:

0.00136

GnomAD2 exomes

AF:

0.00144

AC:

143

AN:

99236

AF XY:

0.00123

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0233

Gnomad NFE exome

AF:

0.000133

Gnomad OTH exome

AF:

0.000650

GnomAD4 exome

AF:

0.000569

AC:

594

AN:

1043543

Hom.:

Cov.:

AF XY:

0.000508

AC XY:

173

AN XY:

340821

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24880

American (AMR)

AF:

0.00

AC:

AN:

27904

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18627

East Asian (EAS)

AF:

0.00

AC:

AN:

27121

South Asian (SAS)

AF:

0.00

AC:

AN:

49854

European-Finnish (FIN)

AF:

0.0188

AC:

532

AN:

28325

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3931

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

818632

Other (OTH)

AF:

0.000452

AC:

AN:

44269

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

114

142

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00110

AC:

120

AN:

109475

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

AN XY:

31963

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30143

American (AMR)

AF:

0.00

AC:

AN:

10616

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2618

East Asian (EAS)

AF:

0.000295

AC:

AN:

3386

South Asian (SAS)

AF:

0.00

AC:

AN:

2467

European-Finnish (FIN)

AF:

0.0173

AC:

101

AN:

5834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

209

European-Non Finnish (NFE)

AF:

0.000307

AC:

AN:

52062

Other (OTH)

AF:

0.00134

AC:

AN:

1490

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.00113

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, X-linked 1 (1)

IQSEC2-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

1.3

PromoterAI

-0.045

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over