X-53248125-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001111125.3(IQSEC2):c.2571C>A(p.Ile857Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,209,385 control chromosomes in the GnomAD database, including 5 homozygotes. There are 392 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I857I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00081 ( 0 hom., 33 hem., cov: 22)

Exomes 𝑓: 0.0010 ( 5 hom. 359 hem. )

Consequence

IQSEC2
NM_001111125.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.294

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 -16 ACMG points.

BP6

Variant X-53248125-G-T is Benign according to our data. Variant chrX-53248125-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 385234.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000814 (91/111839) while in subpopulation NFE AF = 0.00111 (59/53110). AF 95% confidence interval is 0.000884. There are 0 homozygotes in GnomAd4. There are 33 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 33 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.2571C>A	p.Ile857Ile	synonymous	Exon 7 of 15	NP_001104595.1	Q5JU85-2
IQSEC2	NM_001441092.1		c.2571C>A	p.Ile857Ile	synonymous	Exon 7 of 14	NP_001428021.1
IQSEC2	NM_001410736.1		c.2571C>A	p.Ile857Ile	synonymous	Exon 7 of 14	NP_001397665.1	A0A1W2PR28

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IQSEC2	ENST00000642864.1	MANE Select	c.2571C>A	p.Ile857Ile	synonymous	Exon 7 of 15	ENSP00000495726.1	Q5JU85-2
IQSEC2	ENST00000375365.2	TSL:1	c.1956C>A	p.Ile652Ile	synonymous	Exon 7 of 14	ENSP00000364514.2	Q5JU85-3
IQSEC2	ENST00000706952.1		c.2730C>A	p.Ile910Ile	synonymous	Exon 7 of 15	ENSP00000516672.1	A0A9L9PY69

Frequencies

GnomAD3 genomes

AF:

0.000805

AC:

AN:

111786

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000977

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000190

Gnomad ASJ

AF:

0.00753

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000750

Gnomad FIN

AF:

0.000489

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00111

Gnomad OTH

AF:

0.000670

GnomAD2 exomes

AF:

0.000999

AC:

181

AN:

181211

AF XY:

0.00124

show subpopulations

Gnomad AFR exome

AF:

0.0000768

Gnomad AMR exome

AF:

0.000110

Gnomad ASJ exome

AF:

0.00604

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000191

Gnomad NFE exome

AF:

0.00137

Gnomad OTH exome

AF:

0.00179

GnomAD4 exome

AF:

0.00103

AC:

1127

AN:

1097546

Hom.:

Cov.:

AF XY:

0.000989

AC XY:

359

AN XY:

362922

show subpopulations

African (AFR)

AF:

0.000341

AC:

AN:

26392

American (AMR)

AF:

0.000114

AC:

AN:

35176

Ashkenazi Jewish (ASJ)

AF:

0.00666

AC:

129

AN:

19374

East Asian (EAS)

AF:

0.00

AC:

AN:

30198

South Asian (SAS)

AF:

0.000575

AC:

AN:

53917

European-Finnish (FIN)

AF:

0.000247

AC:

AN:

40489

Middle Eastern (MID)

AF:

0.00436

AC:

AN:

4130

European-Non Finnish (NFE)

AF:

0.00101

AC:

852

AN:

841795

Other (OTH)

AF:

0.00161

AC:

AN:

46075

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

126

168

210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<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:

0.000814

AC:

AN:

111839

Hom.:

Cov.:

AF XY:

0.000970

AC XY:

AN XY:

34023

show subpopulations

African (AFR)

AF:

0.000130

AC:

AN:

30773

American (AMR)

AF:

0.000189

AC:

AN:

10558

Ashkenazi Jewish (ASJ)

AF:

0.00753

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3543

South Asian (SAS)

AF:

0.000752

AC:

AN:

2658

European-Finnish (FIN)

AF:

0.000489

AC:

AN:

6129

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.00111

AC:

AN:

53110

Other (OTH)

AF:

0.000662

AC:

AN:

1511

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

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:

0.000910

Hom.:

Bravo

AF:

0.000835

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (2)

Inborn genetic diseases (1)

Intellectual disability, X-linked 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

(source)

DANN

Benign

0.77

PhyloP100

-0.29

PromoterAI

-0.067

Neutral

(source)

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.29

Position offset: 29

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