rs200248561
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Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS1
The NM_001330078.2(NRXN1):āc.501C>Gā(p.Leu167=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,612,478 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0014 ( 1 hom., cov: 33)
Exomes š: 0.00025 ( 1 hom. )
Consequence
NRXN1
NM_001330078.2 synonymous
NM_001330078.2 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.717
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 Benign. Variant got -17 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.51).
BP6
Variant 2-51027773-G-C is Benign according to our data. Variant chr2-51027773-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 138557.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-51027773-G-C is described in Lovd as [Likely_benign].
BP7
Synonymous conserved (PhyloP=0.717 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00137 (208/152280) while in subpopulation AFR AF= 0.00416 (173/41572). AF 95% confidence interval is 0.00366. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NRXN1 | NM_001330078.2 | c.501C>G | p.Leu167= | synonymous_variant | 2/23 | ENST00000401669.7 | NP_001317007.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NRXN1 | ENST00000401669.7 | c.501C>G | p.Leu167= | synonymous_variant | 2/23 | 5 | NM_001330078.2 | ENSP00000385017 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00135 AC: 205AN: 152160Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.000541 AC: 132AN: 244000Hom.: 0 AF XY: 0.000436 AC XY: 58AN XY: 133090
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GnomAD4 exome AF: 0.000253 AC: 369AN: 1460198Hom.: 1 Cov.: 31 AF XY: 0.000229 AC XY: 166AN XY: 726372
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GnomAD4 genome AF: 0.00137 AC: 208AN: 152280Hom.: 1 Cov.: 33 AF XY: 0.00141 AC XY: 105AN XY: 74440
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | NRXN1: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 07, 2017 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
not specified Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 24, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 06, 2015 | - - |
Pitt-Hopkins-like syndrome 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2016 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at