X-53241915-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The ENST00000642864.1(IQSEC2):c.2890-6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,205,627 control chromosomes in the GnomAD database, including 1 homozygotes. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., 10 hem., cov: 22)

Exomes 𝑓: 0.000021 ( 1 hom. 1 hem. )

Consequence

IQSEC2
ENST00000642864.1 splice_region, intron

Scores

Splicing: ADA: 0.0001083

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -3.93

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: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant X-53241915-C-T is Benign according to our data. Variant chrX-53241915-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 538616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 10 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000642864.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IQSEC2	NM_001111125.3	MANE Select	c.2890-6G>A	splice_region intron	N/A	NP_001104595.1
IQSEC2	NM_001441092.1		c.2890-6G>A	splice_region intron	N/A	NP_001428021.1
IQSEC2	NM_001410736.1		c.2890-6G>A	splice_region intron	N/A	NP_001397665.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
IQSEC2	ENST00000642864.1	MANE Select	c.2890-6G>A	splice_region intron	N/A	ENSP00000495726.1
IQSEC2	ENST00000375365.2	TSL:1	c.2275-6G>A	splice_region intron	N/A	ENSP00000364514.2
IQSEC2	ENST00000674761.1		n.1191G>A	non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.000241

AC:

AN:

111857

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000377

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000466

AC:

AN:

171721

AF XY:

0.0000174

show subpopulations

Gnomad AFR exome

AF:

0.000487

Gnomad AMR exome

AF:

0.0000376

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000234

GnomAD4 exome

AF:

0.0000210

AC:

AN:

1093715

Hom.:

Cov.:

AF XY:

0.00000278

AC XY:

AN XY:

359559

show subpopulations

African (AFR)

AF:

0.000456

AC:

AN:

26313

American (AMR)

AF:

0.0000862

AC:

AN:

34807

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19322

East Asian (EAS)

AF:

0.00

AC:

AN:

30066

South Asian (SAS)

AF:

0.00

AC:

AN:

53170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4064

European-Non Finnish (NFE)

AF:

0.00000119

AC:

AN:

839965

Other (OTH)

AF:

0.000152

AC:

AN:

45948

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

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:

0.000241

AC:

AN:

111912

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

AN XY:

34080

show subpopulations

African (AFR)

AF:

0.000747

AC:

AN:

30776

American (AMR)

AF:

0.000377

AC:

AN:

10610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3541

South Asian (SAS)

AF:

0.00

AC:

AN:

2645

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6119

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53153

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.000142

Hom.:

Bravo

AF:

0.000268

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Intellectual disability, X-linked 1 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.12

(source)

DANN

Benign

0.71

PhyloP100

-3.9

PromoterAI

0.0074

Neutral

(source)

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.048

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over