rs146979083

chrX-53248125-G-AchrX-53248125-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_001111125.3(IQSEC2):c.2571C>T(p.Ile857=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,209,335 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. I857I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000015 (0 hom. 8 hem.)
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.294

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 Likely_benign. Variant got -6 ACMG points.

• BP6: Variant X-53248125-G-A is Benign according to our data. Variant chrX-53248125-G-A is described in ClinVar as [Benign]. Clinvar id is 1977180.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IQSEC2	NM_001111125.3	c.2571C>T	p.Ile857=	synonymous_variant	7/15	ENST00000642864.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IQSEC2	ENST00000642864.1	c.2571C>T	p.Ile857=	synonymous_variant	7/15		NM_001111125.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111786 Hom.: 0 Cov.: 22 AF XY: 0.0000294 AC XY: 1 AN XY: 33960

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000377

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000221 AC: 4 AN: 181211 Hom.: 0 AF XY: 0.0000304 AC XY: 2 AN XY: 65887

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000107

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000248

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1097549 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 8 AN XY: 362925

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000143

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111786 Hom.: 0 Cov.: 22 AF XY: 0.0000294 AC XY: 1 AN XY: 33960

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000377

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	8.2
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 29

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

Publications

LitVar

Other links and lift over

dbSNP: rs146979083; hg19: chrX-53277307;