NM_000492.4(CFTR):c.2490+2T>C AND Cystic fibrosis

Germline classification:: Conflicting interpretations of pathogenicity (4 submissions)
Last evaluated:: Jun 21, 2024
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000411517.17

Allele description [Variation Report for NM_000492.4(CFTR):c.2490+2T>C]

NM_000492.4(CFTR):c.2490+2T>C

Gene:

CFTR:CF transmembrane conductance regulator [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

7q31.2

Genomic location:

Preferred name:

NM_000492.4(CFTR):c.2490+2T>C

HGVS:

NC_000007.14:g.117592659T>C
NG_016465.4:g.131876T>C
NM_000492.4:c.2490+2T>CMANE SELECT
LRG_663t1:c.2490+2T>C
LRG_663:g.131876T>C
NC_000007.13:g.117232713T>C
NM_000492.3:c.2490+2T>C

Links:

dbSNP: rs1057516216

NCBI 1000 Genomes Browser:

rs1057516216

Molecular consequence:

NM_000492.4:c.2490+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Cystic fibrosis (CF)
Synonyms:: Mucoviscidosis
Identifiers:: MONDO: MONDO:0009061; MedGen: C0010674; Orphanet: 586; OMIM: 219700

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000485278	Counsyl	criteria provided, single submitter (Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015))	Likely pathogenic (Feb 19, 2016)	unknown	clinical testing	mdi-5618_320494_Counsyl Autosomal and X-linked Recessive Disease Classification criteria (2015).pdf, Citation Link,
SCV001363801	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29879995, 32357917, 31036917 Citation Link,
SCV002182630	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 2, 2021)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 7683952, 23974870, 20059485, 12815607, 9239681, 16199547, 1695717, 7691345, 9725922, 28492532
SCV002741013	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jun 21, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27240813, 31131953 Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases.

Hamdi Y, Boujemaa M, Ben Rekaya M, Ben Hamda C, Mighri N, El Benna H, Mejri N, Labidi S, Daoud N, Naouali C, Messaoud O, Chargui M, Ghedira K, Boubaker MS, Mrad R, Boussen H, Abdelhak S; PEC Consortium..

J Transl Med. 2018 Jun 7;16(1):158. doi: 10.1186/s12967-018-1504-9.

PubMed [citation]

PMID:: 29879995
PMCID:: PMC5992876

The true panel of cystic fibrosis mutations in the Sicilian population.

Chamayou S, Sicali M, Lombardo D, Maglia E, Liprino A, Cardea C, Fichera M, Venti E, Guglielmino A.

BMC Med Genet. 2020 May 1;21(1):89. doi: 10.1186/s12881-020-0958-9.

PubMed [citation]

PMID:: 32357917
PMCID:: PMC7195759

See all PubMed Citations (15)

Details of each submission

From Counsyl, SCV000485278.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001363801.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: CFTR c.2490+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site and three predict the variant strengthens a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 188996 control chromosomes (gnomAD). To our knowledge, no occurrence of c.2490+2T>C in individuals affected with Cystic Fibrosis and no experimental evidence demonstrating its impact on protein function have been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31036917, 32357917, 29879995). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Three submitters classified the variant as pathogenic/likely pathogenic and one classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002182630.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 7683952, 23974870, 20059485, 12815607, 9239681). ClinVar contains an entry for this variant (Variation ID: 370078). This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 14 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002741013.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

The c.2490+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 14 in the CFTR gene. Approximately 1% of human splice donor sites have cytosine at the +2 position, and the G>C substitution at this position may not result in aberrant splicing (Sibley CR et al. Nat Rev Genet, 2016 07;17:407-421; Lin JH et al. Hum Mutat, 2019 10;40:1856-1873). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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