X-53227827-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The ENST00000638869.1(IQSEC2):c.1002G>A(p.Leu334=) 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.00900

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]

ACMG classification

Verdict is Benign. Variant got -11 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.
• BS2: High Hemizygotes in GnomAd at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	XM_006724582.5	c.3636G>A	p.Leu1212=	synonymous_variant	16/16
IQSEC2	XM_047441928.1	c.*19G>A		3_prime_UTR_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000638869.1	c.1002G>A	p.Leu334=	synonymous_variant	9/9	5
IQSEC2	ENST00000639796.1	c.*19G>A		3_prime_UTR_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.000660 AC: 74 AN: 112129 Hom.: 0 Cov.: 23 AF XY: 0.000554 AC XY: 19 AN XY: 34287

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: 76 AN: 63501 Hom.: 0 Cov.: 0 AF XY: 0.00208 AC XY: 23 AN XY: 11059

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: 73 AN: 112183 Hom.: 0 Cov.: 23 AF XY: 0.000553 AC XY: 19 AN XY: 34351

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.: 5

Bravo AF: 0.000835

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2023

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

Other links and lift over

dbSNP: rs189949958; hg19: chrX-53257009;