dbSNP rs781940286: IQSEC2:p.Ser228Ser (chrX-53320440-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001111125.3(IQSEC2):c.684C>T(p.Ser228Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000738 in 1,164,975 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 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).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 2 hem., cov: 23)

Exomes 𝑓: 0.000073 ( 0 hom. 28 hem. )

Consequence

IQSEC2
NM_001111125.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.20

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), Ambry Genetics, G2P
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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.58).

BP6

Variant X-53320440-G-A is Benign according to our data. Variant chrX-53320440-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193167.

BP7

Synonymous conserved (PhyloP=1.2 with no splicing effect.

BS2

High Hemizygotes in GnomAd4 at 2 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.684C>T	p.Ser228Ser	synonymous	Exon 1 of 15	NP_001104595.1	Q5JU85-2
IQSEC2	NM_001441092.1		c.684C>T	p.Ser228Ser	synonymous	Exon 1 of 14	NP_001428021.1
IQSEC2	NM_001410736.1		c.684C>T	p.Ser228Ser	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.684C>T	p.Ser228Ser	synonymous	Exon 1 of 15	ENSP00000495726.1	Q5JU85-2
IQSEC2	ENST00000706952.1		c.843C>T	p.Ser281Ser	synonymous	Exon 1 of 15	ENSP00000516672.1	A0A9L9PY69
IQSEC2	ENST00000674510.1		c.684C>T	p.Ser228Ser	synonymous	Exon 1 of 15	ENSP00000502054.1	Q5JU85-2

Frequencies

GnomAD3 genomes

AF:

0.0000797

AC:

AN:

112979

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000131

Gnomad OTH

AF:

0.00131

GnomAD2 exomes

AF:

0.0000925

AC:

AN:

108095

AF XY:

0.000105

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000518

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000174

Gnomad OTH exome

AF:

0.000638

GnomAD4 exome

AF:

0.0000732

AC:

AN:

1051947

Hom.:

Cov.:

AF XY:

0.0000816

AC XY:

AN XY:

343245

show subpopulations

African (AFR)

AF:

0.0000404

AC:

AN:

24779

American (AMR)

AF:

0.0000717

AC:

AN:

27882

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18594

East Asian (EAS)

AF:

0.00

AC:

AN:

27024

South Asian (SAS)

AF:

0.000120

AC:

AN:

49814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37542

Middle Eastern (MID)

AF:

0.00166

AC:

AN:

3610

European-Non Finnish (NFE)

AF:

0.0000733

AC:

AN:

818455

Other (OTH)

AF:

0.0000452

AC:

AN:

44247

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

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:

0.0000796

AC:

AN:

113028

Hom.:

Cov.:

AF XY:

0.0000569

AC XY:

AN XY:

35176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31239

American (AMR)

AF:

0.00

AC:

AN:

10849

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2772

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6281

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000131

AC:

AN:

53232

Other (OTH)

AF:

0.00130

AC:

AN:

1544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.554

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:

0.000130

Hom.:

Bravo

AF:

0.0000831

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Intellectual disability, X-linked 1 (1)

Tip-toe gait (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

(source)

DANN

Benign

0.93

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(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