Genetic Variant IQSEC2:p.Leu333Leu (chrX-53227827-C-T) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_StrongBP6_ModerateBP7BS1BS2

The ENST00000638869.1(IQSEC2):c.999G>A(p.Leu333Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000848 in 175,684 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 42 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00065 ( 0 hom., 19 hem., cov: 23)

Exomes 𝑓: 0.0012 ( 0 hom. 23 hem. )

Consequence

IQSEC2
ENST00000638869.1 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.00900

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant X-53227827-C-T is Benign according to our data. Variant chrX-53227827-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2660597.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.009 with no splicing effect.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0012 (76/63501) while in subpopulation MID AF= 0.011 (3/272). AF 95% confidence interval is 0.00301. There are 0 homozygotes in gnomad4_exome. There are 23 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
IQSEC2	XM_006724582.5 link	c.3636G>A	p.Leu1212Leu	synonymous_variant	Exon 16 of 16	XP_006724645.1
IQSEC2	XM_047441928.1 link	c.*19G>A		3_prime_UTR_variant	Exon 15 of 15	XP_047297884.1
IQSEC2	XM_006724581.5 link	c.*3906G>A		downstream_gene_variant		XP_006724644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000638869.1 link	c.999G>A	p.Leu333Leu	synonymous_variant	Exon 9 of 9	5		ENSP00000491736.1		A0A1W2PPU7
IQSEC2	ENST00000639796 link	c.*19G>A		3_prime_UTR_variant	Exon 3 of 3	3		ENSP00000492252.1		A0A1W2PQS2

Frequencies

GnomAD3 genomes

AF:

0.000660

AC:

AN:

112129

Hom.:

Cov.:

AF XY:

0.000554

AC XY:

AN XY:

34287

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000940

Gnomad ASJ

AF:

0.00303

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000745

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.000771

Gnomad OTH

AF:

0.00330

GnomAD4 exome

AF:

0.00120

AC:

AN:

63501

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

AN XY:

11059

show subpopulations

Gnomad4 AFR exome

AF:

0.000821

Gnomad4 AMR exome

AF:

0.00204

Gnomad4 ASJ exome

AF:

0.00458

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00106

Gnomad4 OTH exome

AF:

0.00281

GnomAD4 genome

AF:

0.000651

AC:

AN:

112183

Hom.:

Cov.:

AF XY:

0.000553

AC XY:

AN XY:

34351

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.000939

Gnomad4 ASJ

AF:

0.00303

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000747

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000771

Gnomad4 OTH

AF:

0.00326

Alfa

AF:

0.00128

Hom.:

Bravo

AF:

0.000835

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KDM5C: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.3

DANN

Benign

0.58

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over