Genetic Variant IQSEC2:p.Val1006Val (chrX-53239292-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6BP7

The NM_001111125.3(IQSEC2):c.3018C>A(p.Val1006Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000338 in 1,185,119 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.0000028 ( 0 hom. 0 hem. )

Consequence

IQSEC2
NM_001111125.3 splice_region, synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.564

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 -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.38).

BP6

Variant X-53239292-G-T is Benign according to our data. Variant chrX-53239292-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211202.

BP7

Synonymous conserved (PhyloP=0.564 with no splicing effect.

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.3018C>A	p.Val1006Val	splice_region synonymous	Exon 11 of 15	NP_001104595.1
IQSEC2	NM_001441092.1		c.3018C>A	p.Val1006Val	splice_region synonymous	Exon 11 of 14	NP_001428021.1
IQSEC2	NM_001410736.1		c.3018C>A	p.Val1006Val	splice_region synonymous	Exon 11 of 14	NP_001397665.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
IQSEC2	ENST00000642864.1	MANE Select	c.3018C>A	p.Val1006Val	splice_region synonymous	Exon 11 of 15	ENSP00000495726.1
IQSEC2	ENST00000375365.2	TSL:1	c.2403C>A	p.Val801Val	splice_region synonymous	Exon 11 of 14	ENSP00000364514.2
IQSEC2	ENST00000706952.1		c.3177C>A	p.Val1059Val	splice_region synonymous	Exon 11 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes

AF:

0.00000900

AC:

AN:

111139

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:

0.000284

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000220

AC:

AN:

181635

AF XY:

0.0000151

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000290

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000279

AC:

AN:

1073980

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

340312

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25937

American (AMR)

AF:

0.00

AC:

AN:

35138

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19207

East Asian (EAS)

AF:

0.0000997

AC:

AN:

30095

South Asian (SAS)

AF:

0.00

AC:

AN:

53414

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40223

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3978

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

820655

Other (OTH)

AF:

0.00

AC:

AN:

45333

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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:

0.00000900

AC:

AN:

111139

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33353

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30494

American (AMR)

AF:

0.00

AC:

AN:

10448

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.000284

AC:

AN:

3524

South Asian (SAS)

AF:

0.00

AC:

AN:

2622

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5987

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53012

Other (OTH)

AF:

0.00

AC:

AN:

1489

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.675

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 29, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Intellectual disability, X-linked 1

Benign:1

Jul 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.56

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over