Genetic Variant IQSEC2:p.Ile1431Ile (chrX-53234393-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_001111125.3(IQSEC2):c.4293C>T(p.Ile1431Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. 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 0.00015 ( 0 hom., 1 hem., cov: 11)

Exomes 𝑓: 0.00023 ( 0 hom. 38 hem. )

Failed GnomAD Quality Control

Consequence

IQSEC2
NM_001111125.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.06

Publications

1 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

new If you want to explore the variant's impact on the transcript NM_001111125.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.67).

BP6

Variant X-53234393-G-A is Benign according to our data. Variant chrX-53234393-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194482.

BP7

Synonymous conserved (PhyloP=2.06 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000147 (10/68188) while in subpopulation EAS AF = 0.0064 (10/1562). AF 95% confidence interval is 0.00347. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 11. This position passed quality control check.

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.4293C>T	p.Ile1431Ile	synonymous	Exon 15 of 15	NP_001104595.1	Q5JU85-2
IQSEC2	NM_001410736.1		c.*778C>T		3_prime_UTR	Exon 14 of 14	NP_001397665.1	A0A1W2PR28
IQSEC2	NM_001441093.1		c.*778C>T		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQSEC2	ENST00000642864.1	MANE Select	c.4293C>T	p.Ile1431Ile	synonymous	Exon 15 of 15	ENSP00000495726.1	Q5JU85-2
IQSEC2	ENST00000375365.2	TSL:1	c.*778C>T		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2	Q5JU85-3
IQSEC2	ENST00000706952.1		c.4452C>T	p.Ile1484Ile	synonymous	Exon 15 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes

AF:

0.000147

AC:

AN:

68156

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:

0.00639

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:

0.000374

AC:

AN:

24049

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00380

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000228

AC:

123

AN:

540478

Hom.:

Cov.:

AF XY:

0.000329

AC XY:

AN XY:

115636

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

11436

American (AMR)

AF:

0.00

AC:

AN:

7085

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7092

East Asian (EAS)

AF:

0.00760

AC:

AN:

12765

South Asian (SAS)

AF:

0.000713

AC:

AN:

19648

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21597

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1261

European-Non Finnish (NFE)

AF:

0.00000914

AC:

AN:

437509

Other (OTH)

AF:

0.000362

AC:

AN:

22085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000147

AC:

AN:

68188

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

8654

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18038

American (AMR)

AF:

0.00

AC:

AN:

5749

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1793

East Asian (EAS)

AF:

0.00640

AC:

AN:

1562

South Asian (SAS)

AF:

0.00

AC:

AN:

716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2467

Middle Eastern (MID)

AF:

0.00

AC:

AN:

117

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

36461

Other (OTH)

AF:

0.00

AC:

AN:

858

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

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:

0.000337

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Inborn genetic diseases (1)

Intellectual disability, X-linked 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

4.7

(source)

DANN

Benign

0.69

PhyloP100

2.1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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