rs184248834

Variant names:

• chrX-53241915-C-G
• rs184248834
• NM_001111125.3:c.2890-6G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-53241915-C-G
• chrX-53241915-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001111125.3(IQSEC2):​c.2890-6G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000914 in 1,093,715 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002881
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.93
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).

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

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

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.14e-7 AC: 1 AN: 1093715 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 359559

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26313

American (AMR) AF: 0.00 AC: 0 AN: 34807

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19322

East Asian (EAS) AF: 0.00 AC: 0 AN: 30066

South Asian (SAS) AF: 0.00 AC: 0 AN: 53170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4064

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839965

Other (OTH) AF: 0.00 AC: 0 AN: 45948

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.099
DANN	Benign	0.61
PhyloP100		-3.9
PromoterAI		0.0072	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0080
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

Other links and lift over

dbSNP: rs184248834; hg19: chrX-53271097;