rs61745228

Positions:

• chrX-53250935-C-G
• chrX-53250935-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_001111125.3(IQSEC2):​c.1641G>C​(p.Ala547=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000043 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: IQSEC2 NM_001111125.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.929

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP7: Synonymous conserved (PhyloP=0.929 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IQSEC2	NM_001111125.3	c.1641G>C	p.Ala547=	synonymous_variant	5/15	ENST00000642864.1	NP_001104595.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IQSEC2	ENST00000642864.1	c.1641G>C	p.Ala547=	synonymous_variant	5/15		NM_001111125.3	ENSP00000495726	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.000474 AC: 77 AN: 162299 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 56191

Gnomad AFR exome AF: 0.000713

Gnomad AMR exome AF: 0.000230

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000593

Gnomad FIN exome AF: 0.00115

Gnomad NFE exome AF: 0.000596

Gnomad OTH exome AF: 0.000978

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000433 AC: 47 AN: 1086480 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 356084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000118

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000383

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.0000203

Gnomad4 OTH exome AF: 0.0000439

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	2.1
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs61745228; hg19: chrX-53280117;