chr2-51027609-TCCTCGCCCG-T
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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):βc.656_664delβ(p.Ala219_Glu221del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000602 in 1,593,602 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000046 ( 0 hom., cov: 33)
Exomes π: 0.000062 ( 1 hom. )
Consequence
NRXN1
NM_001330078.2 inframe_deletion
NM_001330078.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.96
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.656_664del | p.Ala219_Glu221del | inframe_deletion | 2/23 | ENST00000401669.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRXN1 | ENST00000401669.7 | c.656_664del | p.Ala219_Glu221del | inframe_deletion | 2/23 | 5 | NM_001330078.2 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152032Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000623 AC: 13AN: 208558Hom.: 0 AF XY: 0.0000966 AC XY: 11AN XY: 113898
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GnomAD4 exome AF: 0.0000617 AC: 89AN: 1441452Hom.: 1 AF XY: 0.0000643 AC XY: 46AN XY: 715180
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GnomAD4 genome AF: 0.0000460 AC: 7AN: 152150Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5AN XY: 74384
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 30, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2023 | Identified in one individual with non-syndromic intellectual disability and was paternally inherited, however, no additional information was provided (Gauthier et al., 2011); In silico analysis supports that this variant does not alter protein structure/function; In-frame deletion of 3 amino acids in a non-repeat region; This variant is associated with the following publications: (PMID: 21424692) - |
Pitt-Hopkins-like syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This variant, c.656_664del, results in the deletion of 3 amino acid(s) of the NRXN1 protein (p.Ala219_Glu221del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs546508545, gnomAD 0.01%). This variant has been observed in individual(s) with NRXN1-related conditions (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 452464). 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. - |
NRXN1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 14, 2023 | The NRXN1 c.656_664del9 variant is predicted to result in an in-frame deletion (p.Ala219_Glu221del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-51254747-TCCTCGCCCG-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at