VCV001048080.5 - ClinVar

NM_001351169.2(NT5C2):c.1449+2T>C

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.

(3)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001351169.2(NT5C2):c.1449+2T>C

Variation ID: 1048080 Accession: VCV001048080.5

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q24.32 10: 103090609 (GRCh38) [ NCBI UCSC ] 10: 104850366 (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	Mar 28, 2021	Nov 11, 2023	Feb 23, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001351169.2:c.1449+2T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice donor
NM_001134373.3:c.1449+2T>C		splice donor
NM_001351170.2:c.1473+2T>C		splice donor
NM_001351171.2:c.1473+2T>C		splice donor
NM_001351172.2:c.1473+2T>C		splice donor
NM_001351173.2:c.1473+2T>C		splice donor
NM_001351174.1:c.1362+2T>C		splice donor
NM_001351175.2:c.1356+2T>C		splice donor
NM_001351176.2:c.876+2T>C		splice donor
NM_001351177.2:c.876+2T>C		splice donor
NM_001351178.2:c.876+2T>C		splice donor
NM_001351179.2:c.876+2T>C		splice donor
NM_001351180.2:c.876+2T>C		splice donor
NM_001351181.2:c.876+2T>C		splice donor
NM_001351182.2:c.876+2T>C		splice donor
NM_001351183.2:c.876+2T>C		splice donor
NM_001351184.2:c.876+2T>C		splice donor
NM_001351185.2:c.876+2T>C		splice donor
NM_001351186.2:c.876+2T>C		splice donor
NM_001351187.2:c.876+2T>C		splice donor
NM_001351188.2:c.876+2T>C		splice donor
NM_001351189.2:c.876+2T>C		splice donor
NM_001351190.2:c.876+2T>C		splice donor
NM_001351191.1:c.876+2T>C		splice donor
NM_001351192.1:c.876+2T>C		splice donor
NM_001351193.1:c.876+2T>C		splice donor
NM_001351194.2:c.735+2T>C		splice donor
NM_001351195.2:c.735+2T>C		splice donor
NM_001351196.2:c.735+2T>C		splice donor
NM_001351197.2:c.876+2T>C		splice donor
NM_012229.5:c.1449+2T>C		splice donor
NC_000010.11:g.103090609A>G
NC_000010.10:g.104850366A>G
NG_031932.2:g.177317A>G
NG_042272.1:g.107698T>C

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000010.11:103090608:A:G

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.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

dbSNP: rs753295868 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.
NT5C2		-	-	GRCh38 GRCh37	204	267

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.
Hereditary spastic paraplegia 45	Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Feb 23, 2023	RCV001352898.3
Neurodevelopmental disorder	Pathogenic (1)	criteria provided, single submitter	Jan 17, 2023	RCV002276708.2

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.
Likely pathogenic (Mar 05, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 45 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breda Genetics srl Accession: SCV001547508.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Comment: The variant c.1449+2T>C in the NT5C2 gene affects the donor splice site of intron 18 and is therefore highly likely to impact the splicing process … (more) The variant c.1449+2T>C in the NT5C2 gene affects the donor splice site of intron 18 and is therefore highly likely to impact the splicing process by causing the retention of the following intron and the formation of an aberrant mRNA, which is unlikely to be exported and translated into protein. The variant is reported with an estimated allele frequency of 0.000004 in gnomAD exomes (1/249214 alleles) with no homozygous individuals reported. The mutational spectrum of spinocerebellar ataxia 45 includes both protein-disrupting and missense variants. (less)
Likely pathogenic (Feb 23, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary spastic paraplegia 45 Affected status: yes Allele origin: unknown	3billion Accession: SCV003841869.1 First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023	Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to alter splicing … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001048080). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Spastic paraplegia (present) , Rigidity (present)
Pathogenic (Jan 17, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neurodevelopmental disorder Affected status: yes Allele origin: germline	Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes Accession: SCV002564494.2 First in ClinVar: Aug 29, 2022 Last updated: Nov 11, 2023

Comment:

The variant c.1449+2T>C in the NT5C2 gene affects the donor splice site of intron 18 and is therefore highly likely to impact the splicing process by causing the retention of the following intron and the formation of an aberrant mRNA, which is unlikely to be exported and translated into protein. The variant is reported with an estimated allele frequency of 0.000004 in gnomAD exomes (1/249214 alleles) with no homozygous individuals reported. The mutational spectrum of spinocerebellar ataxia 45 includes both protein-disrupting and missense variants.

Comment:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. The predicted truncated protein may be shortened by more than 10%. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV001048080). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.

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 rs753295868 ...

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 11, 2023

ClinVar Genomic variation as it relates to human health

NM_001351169.2(NT5C2):c.1449+2T>C

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs753295868 ...