ClinVar Genomic variation as it relates to human health
NM_001330078.2(NRXN1):c.1945A>G (p.Ile649Val)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(6); Benign(1); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001330078.2(NRXN1):c.1945A>G (p.Ile649Val)
Variation ID: 167387 Accession: VCV000167387.46
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 2p16.3 2: 50538451 (GRCh38) [ NCBI UCSC ] 2: 50765589 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 5, 2015 Apr 15, 2024 Feb 21, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001330078.2:c.1945A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001317007.1:p.Ile649Val missense NM_001135659.2:c.2065A>G NM_001135659.3:c.2065A>G NP_001129131.1:p.Ile689Val missense NM_001330077.2:c.1921A>G NP_001317006.1:p.Ile641Val missense NM_001330082.2:c.1921A>G NP_001317011.1:p.Ile641Val missense NM_001330083.2:c.1906A>G NP_001317012.1:p.Ile636Val missense NM_001330084.2:c.1906A>G NP_001317013.1:p.Ile636Val missense NM_001330085.2:c.1945A>G NP_001317014.1:p.Ile649Val missense NM_001330086.2:c.1945A>G NP_001317015.1:p.Ile649Val missense NM_001330087.2:c.1861A>G NP_001317016.1:p.Ile621Val missense NM_001330088.2:c.1891A>G NP_001317017.1:p.Ile631Val missense NM_001330093.2:c.1942A>G NP_001317022.1:p.Ile648Val missense NM_001330094.2:c.1933A>G NP_001317023.1:p.Ile645Val missense NM_001330095.2:c.1921A>G NP_001317024.1:p.Ile641Val missense NM_001330096.2:c.1861A>G NP_001317025.1:p.Ile621Val missense NM_004801.6:c.1945A>G NP_004792.1:p.Ile649Val missense NC_000002.12:g.50538451T>C NC_000002.11:g.50765589T>C NG_011878.1:g.499086A>G - Protein change
- I689V, I645V, I648V, I649V, I641V, I621V, I631V, I636V
- Other names
- p.I689V:ATC>GTC
- Canonical SPDI
- NC_000002.12:50538450:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
The Genome Aggregation Database (gnomAD) 0.00062
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00040
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00046
Exome Aggregation Consortium (ExAC) 0.00065
The Genome Aggregation Database (gnomAD), exomes 0.00049
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NRXN1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2274 | 2339 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Uncertain significance (1) |
criteria provided, single submitter
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Dec 16, 2014 | RCV000188230.19 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
|
Jan 27, 2024 | RCV000649744.23 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Feb 16, 2021 | RCV000723794.30 | |
Likely benign (1) |
criteria provided, single submitter
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Apr 4, 2019 | RCV002316970.8 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 21, 2024 | RCV003927485.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(Dec 16, 2014)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000248276.1
First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015 |
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Uncertain significance
(Sep 01, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000203142.7
First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Uncertain significance
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001304009.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
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 … (more)
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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
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Uncertain significance
(Apr 08, 2018)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Affected status: yes
Allele origin:
unknown
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Baylor Genetics
Accession: SCV001529577.1
First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely benign
(Feb 16, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000241837.13
First in ClinVar: Aug 07, 2015 Last updated: Apr 17, 2019 |
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Likely benign
(Apr 04, 2019)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000851237.4
First in ClinVar: Nov 08, 2018 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: 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. (less)
Number of individuals with the variant: 1
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Benign
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins-like syndrome 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000771576.8
First in ClinVar: May 28, 2018 Last updated: Feb 28, 2024 |
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Uncertain significance
(Feb 21, 2024)
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criteria provided, single submitter
Method: clinical testing
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NRXN1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004746756.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The NRXN1 c.2065A>G variant is predicted to result in the amino acid substitution p.Ile689Val. To our knowledge, this variant has not been reported in the … (more)
The NRXN1 c.2065A>G variant is predicted to result in the amino acid substitution p.Ile689Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which is likely too common to be an unreported cause of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Jul 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001152307.21
First in ClinVar: Feb 03, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Study: VKGL Data-share Consensus
Accession: SCV001799555.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021 |
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001975918.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=NRXN1 | - | - | - | - |
Text-mined citations for rs200074974 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.