VCV000755691.14 - ClinVar

NM_001363.5(DKC1):c.915+10G>A

Germline

Classification

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.

(4)

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.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001363.5(DKC1):c.915+10G>A

Variation ID: 755691 Accession: VCV000755691.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: Xq28 X: 154769320 (GRCh38) [ NCBI UCSC ] X: 153997595 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 17, 2019	Oct 8, 2024	Nov 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001363.5:c.915+10G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001142463.3:c.915+10G>A		intron variant
NM_001288747.2:c.915+10G>A		intron variant
NC_000023.11:g.154769320G>A
NC_000023.10:g.153997595G>A
NG_009780.1:g.11565G>A
LRG_55:g.11565G>A
LRG_55t1:c.915+10G>A

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000023.11:154769319:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1603429509 VarSome

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
Gene	OMIM	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.
DKC1		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	466	681

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.
not provided	Likely pathogenic (1)	criteria provided, single submitter	Nov 21, 2023	RCV000933136.10
not specified	Uncertain significance (1)	criteria provided, single submitter	Oct 26, 2017	RCV001818904.4
Dyskeratosis congenita	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Sep 30, 2021	RCV002066121.7

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.
Uncertain significance (Oct 26, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002071615.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely benign (Sep 30, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Dyskeratosis congenita Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002362930.2 First in ClinVar: Apr 08, 2022 Last updated: Apr 09, 2023
Uncertain significance (Dec 15, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Dyskeratosis congenita Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002684831.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: The c.915+10G>A intronic variant results from a G to A substitution 10 nucleotides after coding exon 9 in the DKC1 gene. This variant was identified … (more) The c.915+10G>A intronic variant results from a G to A substitution 10 nucleotides after coding exon 9 in the DKC1 gene. This variant was identified in a male tested for dyskeratosis congenita in our laboratory and familial testing indicated the alteration was maternally inherited; however, specifc clinical information was not provided. 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 6503 samples with coverage at this position. This nucleotide position is not well conserved in available vertebrate species. In addition, A is the reference nucleotide in at least 5 species. Using the BDGP and ESEfinder splice site prediction tools, this alteration may strengthen a cryptic alternate donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. (less)
Likely pathogenic (Nov 21, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002074050.4 First in ClinVar: Feb 11, 2022 Last updated: Oct 08, 2024	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the … (more) Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32123317, Oquendo2023[Functional Study]) (less)

Comment:

The c.915+10G>A intronic variant results from a G to A substitution 10 nucleotides after coding exon 9 in the DKC1 gene. This variant was identified in a male tested for dyskeratosis congenita in our laboratory and familial testing indicated the alteration was maternally inherited; however, specifc clinical information was not provided. 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 6503 samples with coverage at this position. This nucleotide position is not well conserved in available vertebrate species. In addition, A is the reference nucleotide in at least 5 species. Using the BDGP and ESEfinder splice site prediction tools, this alteration may strengthen a cryptic alternate donor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32123317, Oquendo2023[Functional Study])

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.

Comment:

Citations for germline classification of this variant

There 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 rs1603429509 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001363.5(DKC1):c.915+10G>A

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1603429509 ...