NM_000492.4(CFTR):c.4242+2T>C AND Cystic fibrosis

Germline classification:: Pathogenic/Likely pathogenic (4 submissions)
Last evaluated:: Jan 16, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000029539.7

Allele description [Variation Report for NM_000492.4(CFTR):c.4242+2T>C]

NM_000492.4(CFTR):c.4242+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.4242+2T>C

HGVS:

NC_000007.14:g.117665566T>C
NG_016465.4:g.204783T>C
NM_000492.4:c.4242+2T>CMANE SELECT
LRG_663t1:c.4242+2T>C
LRG_663:g.204783T>C
NC_000007.13:g.117305620T>C
NM_000492.3:c.4242+2T>C

Links:

dbSNP: rs193922526

NCBI 1000 Genomes Browser:

rs193922526

Molecular consequence:

NM_000492.4:c.4242+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

Recent activity

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low-density lipoprotein receptor-related protein 1B precursor [Homo sapiens]
low-density lipoprotein receptor-related protein 1B precursor [Homo sapiens]
gi|93102379|ref|NP_061027.2|

Protein
Chain G, 28S ribosomal protein S9, mitochondrial
Chain G, 28S ribosomal protein S9, mitochondrial
gi|2413506454|pdb|8CSU|G

Protein
Chain U, 28S ribosomal protein S26, mitochondrial
Chain U, 28S ribosomal protein S26, mitochondrial
gi|2413506468|pdb|8CSU|U

Protein
1998-6688[ISSN] (0)
NLM Catalog
probable protein phosphatase 2C 59 isoform X1 [Cucurbita pepo subsp. pepo]
probable protein phosphatase 2C 59 isoform X1 [Cucurbita pepo subsp. pepo]
gi|1333124241|ref|XP_023536554.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000052191	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	likely pathogenic (Aug 18, 2011)	germline	curation	Citation Link,
SCV001456317	Natera, Inc.	no assertion criteria provided	Likely pathogenic (Sep 16, 2020)	germline	clinical testing
SCV002630543	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Nov 14, 2017)	germline	clinical testing	Citation Link,
SCV004675881	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 16, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17576681, 9536098, 1379210, 7682196, 15074370, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	curation
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000052191.2

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

Description

Converted during submission to Likely pathogenic.

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

From Natera, Inc., SCV001456317.1

#	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	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Ambry Genetics, SCV002630543.2

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

Description

The c.4242+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 26 in the CFTR gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is 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, SCV004675881.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). ClinVar contains an entry for this variant (Variation ID: 35884). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 1379210, 7682196, 15074370). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 26 of the CFTR gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product.

#	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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