rs797045628

Variant names:

• chrX-53235069-C-A
• rs797045628
• NM_001111125.3:c.3617G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-53235069-C-A
• chrX-53235069-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001111125.3(IQSEC2):​c.3617G>T​(p.Gly1206Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000949 in 1,053,344 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G1206A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 9.5e-7 (0 hom. 0 hem.)
• Consequence: IQSEC2 NM_001111125.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.35
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3617G>T	p.Gly1206Val	missense	Exon 15 of 15	NP_001104595.1
	IQSEC2	NM_001410736.1		c.*102G>T		3_prime_UTR	Exon 14 of 14	NP_001397665.1
	IQSEC2	NM_001441093.1		c.*102G>T		3_prime_UTR	Exon 14 of 14	NP_001428022.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IQSEC2	ENST00000642864.1	MANE Select	c.3617G>T	p.Gly1206Val	missense	Exon 15 of 15	ENSP00000495726.1
	IQSEC2	ENST00000375365.2	TSL:1	c.*102G>T		3_prime_UTR	Exon 14 of 14	ENSP00000364514.2
	IQSEC2	ENST00000706952.1		c.3776G>T	p.Gly1259Val	missense	Exon 15 of 15	ENSP00000516672.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 9.49e-7 AC: 1 AN: 1053344 Hom.: 0 Cov.: 47 AF XY: 0.00 AC XY: 0 AN XY: 344554

African (AFR) AF: 0.00 AC: 0 AN: 24893

American (AMR) AF: 0.00 AC: 0 AN: 27901

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18632

East Asian (EAS) AF: 0.00 AC: 0 AN: 27136

South Asian (SAS) AF: 0.00 AC: 0 AN: 49856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37599

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3521

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 819498

Other (OTH) AF: 0.00 AC: 0 AN: 44308

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.040	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	-0.21	T
PhyloP100		7.4
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0060	D
Vest4		0.49
MutPred		0.28		Gain of catalytic residue at G1206 (P = 0.0361)
MVP		0.47
MPC		2.0
ClinPred		1.0	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.42
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs797045628; hg19: chrX-53264251;