ClinVar Genomic variation as it relates to human health
NM_006846.4(SPINK5):c.2243A>G (p.Glu748Gly)
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(2); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006846.4(SPINK5):c.2243A>G (p.Glu748Gly)
Variation ID: 449103 Accession: VCV000449103.25
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q32 5: 148118988 (GRCh38) [ NCBI UCSC ] 5: 147498551 (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 Dec 19, 2017 Apr 15, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006846.4:c.2243A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006837.2:p.Glu748Gly missense NM_001127698.2:c.2243A>G NP_001121170.1:p.Glu748Gly missense NM_001127699.2:c.2243A>G NP_001121171.1:p.Glu748Gly missense NC_000005.10:g.148118988A>G NC_000005.9:g.147498551A>G NG_009633.1:g.60017A>G LRG_110:g.60017A>G LRG_110t1:c.2243A>G LRG_110p1:p.Glu748Gly - Protein change
- E748G
- Other names
- -
- Canonical SPDI
- NC_000005.10:148118987:A:G
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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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0.00220 (G)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00187
1000 Genomes Project 0.00220
The Genome Aggregation Database (gnomAD), exomes 0.00292
Trans-Omics for Precision Medicine (TOPMed) 0.00295
The Genome Aggregation Database (gnomAD) 0.00297
Exome Aggregation Consortium (ExAC) 0.00314
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00403
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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SPINK5 | - | - |
GRCh38 GRCh37 |
1018 | 1035 |
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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 1, 2023 | RCV000519025.9 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Mar 30, 2021 | RCV000530328.19 | |
Uncertain significance (1) |
no assertion criteria provided
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Apr 18, 2020 | RCV001260963.1 | |
Benign (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV003762759.1 |
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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Likely benign
(Oct 09, 2014)
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criteria provided, single submitter
Method: clinical testing
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Netherton syndrome
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV000743992.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Likely benign
(Jul 27, 2016)
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criteria provided, single submitter
Method: clinical testing
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Netherton syndrome
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Study: VKGL Data-share Consensus
Accession: SCV000745452.1 First in ClinVar: Apr 19, 2018 Last updated: Apr 19, 2018 |
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Uncertain significance
(Aug 29, 2017)
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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: SCV000616884.2
First in ClinVar: Dec 19, 2017 Last updated: Dec 19, 2017 |
Comment:
The E748G variant has been observed as heterozygous with no other SPINK5 variants in a single patient; the patient was published in a meeting abstract … (more)
The E748G variant has been observed as heterozygous with no other SPINK5 variants in a single patient; the patient was published in a meeting abstract (Kumar, et al., 2009). The variant is observed in 304/66700 (0.456%) alleles from individuals of European background in the ExAC dataset, including two homozygotes (Lek et al., 2016). E748G is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Netherton syndrome
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001314443.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Netherton syndrome
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV001190466.2
First in ClinVar: Dec 17, 2019 Last updated: May 06, 2023 |
Comment:
SPINK5 NM_006846.3 exon 24 p.Glu748Gly (c.2243A>G): This variant has not been reported in the literature but is present in 0.3% (123/35358) of Latino alleles, including … (more)
SPINK5 NM_006846.3 exon 24 p.Glu748Gly (c.2243A>G): This variant has not been reported in the literature but is present in 0.3% (123/35358) of Latino alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/5-147498551-A-G). This variant is present in ClinVar (Variation ID:449103). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Benign
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Ichthyosis linearis circumflexa
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000631295.8
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
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Likely benign
(Apr 01, 2023)
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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: SCV004157295.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
FBXO38-DT: BS2; SPINK5: BP4, BS2
Number of individuals with the variant: 2
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Likely benign
(-)
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no assertion criteria provided
Method: clinical testing
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Netherton syndrome
Affected status: yes
Allele origin:
germline
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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV000734387.1 First in ClinVar: Apr 09, 2018 Last updated: Apr 09, 2018 |
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Uncertain significance
(Apr 18, 2020)
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no assertion criteria provided
Method: research
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Susceptibility to nonsyndromic otitis media
Affected status: yes
Allele origin:
germline
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Santos-Cortez Lab, University of Colorado School of Medicine
Accession: SCV001338941.1
First in ClinVar: Oct 23, 2020 Last updated: Oct 23, 2020 |
Ethnicity/Population group: Finnish
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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: SCV001799677.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for rs181639116 ...
HelpRecord last updated Apr 15, 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.