rs774230140
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4
The NM_001330078.2(NRXN1):c.673_674insAGGGCGAGG(p.Glu222_Glu224dup) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.0000187 in 1,601,738 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G225G) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
NRXN1
NM_001330078.2 inframe_insertion
NM_001330078.2 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.97
Genes affected
NRXN1 (HGNC:8008): (neurexin 1) This gene encodes a single-pass type I membrane protein that belongs to the neurexin family. Neurexins are cell-surface receptors that bind neuroligins to form Ca(2+)-dependent neurexin/neuroligin complexes at synapses in the central nervous system. This complex is required for efficient neurotransmission and is involved in the formation of synaptic contacts. Three members of this gene family have been studied in detail and are estimated to generate over 3,000 variants through the use of two alternative promoters (alpha and beta) and extensive alternative splicing in each family member. Recently, a third promoter (gamma) was identified for this gene in the 3' region. Mutations in this gene are associated with Pitt-Hopkins-like syndrome-2 and may contribute to susceptibility to schizophrenia. [provided by RefSeq, Aug 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_001330078.2.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRXN1 | NM_001330078.2 | c.673_674insAGGGCGAGG | p.Glu222_Glu224dup | inframe_insertion | 2/23 | ENST00000401669.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRXN1 | ENST00000401669.7 | c.673_674insAGGGCGAGG | p.Glu222_Glu224dup | inframe_insertion | 2/23 | 5 | NM_001330078.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152180Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000404 AC: 9AN: 222698Hom.: 0 AF XY: 0.0000493 AC XY: 6AN XY: 121790
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GnomAD4 exome AF: 0.0000179 AC: 26AN: 1449442Hom.: 0 Cov.: 31 AF XY: 0.0000208 AC XY: 15AN XY: 719820
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152296Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74460
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 23, 2021 | In-frame insertion of 3 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 20, 2019 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 04, 2016 | The c.665_673dupAGGGCGAGG variant (also known as p.E222_E224dup), located in coding exon 1 of the NRXN1 gene, results from an in-frame duplication of AGGGCGAGG at nucleotide positions 665 to 673. This results in the duplication of 3 extra residues (EGE) between codons 222 and 224. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6334 samples (12668 alleles) with coverage at this position. This amino acid positions are not well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. - |
Pitt-Hopkins-like syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This variant, c.665_673dup, results in the insertion of 3 amino acid(s) of the NRXN1 protein (p.Glu222_Glu224dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs774230140, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NRXN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 539879). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Pitt-Hopkins-like syndrome 2;C3808494:Chromosome 2p16.3 deletion syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | NRXN1 NM_001135659.2 exon 2 p.Glu222_Glu224dup (c.665_673dup): This variant has not been reported in the literature but is present in 9/32736 Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs774230140). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents an in-frame duplication of 3 amino acids at position 222 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at