NM_000492.4:c.1393-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_ModeratePP5_Very_Strong

The NM_000492.4(CFTR):​c.1393-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,593,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

CFTR
NM_000492.4 splice_acceptor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 8.79

Publications

2 publications found
Variant links:
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.043214045 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PP5
Variant 7-117559462-A-G is Pathogenic according to our data. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117559462-A-G is described in CliVar as Pathogenic. Clinvar id is 53243.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.1393-2A>G splice_acceptor_variant, intron_variant Intron 10 of 26 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730
CFTR-AS1NR_149084.1 linkn.221+1271T>C intron_variant Intron 2 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.1393-2A>G splice_acceptor_variant, intron_variant Intron 10 of 26 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251182
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000347
AC:
5
AN:
1441438
Hom.:
0
Cov.:
27
AF XY:
0.00000278
AC XY:
2
AN XY:
718664
show subpopulations
African (AFR)
AF:
0.0000307
AC:
1
AN:
32604
American (AMR)
AF:
0.00
AC:
0
AN:
44700
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26038
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39536
South Asian (SAS)
AF:
0.00
AC:
0
AN:
85804
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53200
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5734
European-Non Finnish (NFE)
AF:
0.00000366
AC:
4
AN:
1094156
Other (OTH)
AF:
0.00
AC:
0
AN:
59666
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.495
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74346
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41462
American (AMR)
AF:
0.00
AC:
0
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3466
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5192
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68010
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.0000140
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:6
Mar 17, 2017
CFTR2
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:research

- -

Jun 13, 2022
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.1393-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 11 in the CFTR gene. The pathogenic mutation was identified in a white male who had meconium ileus, positive sweat test, and chronic lung disease typical of p.F508del homozygotes (Braun AT et al., J. Cyst. Fibros. 2006 Jan; 5(1):33-41). This mutation was also found on three alleles of 148 Norwegian individuals with cystic fibrosis (Munthe-Kaas MC et al., Respir Med 2006 Dec; 100(12):2121-8.). In addition to the clinical data presented in the literature, 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 a disease-causing mutation. -

Jul 01, 2022
CFTR-France
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

- -

Jun 06, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: CFTR c.1393-2A>G 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 a 3' acceptor site. The variant allele was found at a frequency of 8e-06 in 251182 control chromosomes (gnomAD). c.1393-2A>G has been reported in the literature in multiple compound heterozygous individuals affected with Cystic Fibrosis (e.g. Le Marechal_2001, Braun_2006, Green_2010, McCague_2019, Schamschula_2021). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters have assessed the variant since 2014: all four classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 22, 2016
Counsyl
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 06, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 53243). This variant is also known as 1525-2A>G. Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 11379874, 16275171, 16678395). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs397508201, gnomAD 0.007%). This sequence change affects an acceptor splice site in intron 10 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). For these reasons, this variant has been classified as Pathogenic. -

CFTR-related disorder Pathogenic:1
Mar 17, 2017
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.34
CADD
Pathogenic
28
DANN
Uncertain
0.99
Eigen
Pathogenic
1.2
Eigen_PC
Pathogenic
1.0
FATHMM_MKL
Pathogenic
0.99
D
PhyloP100
8.8
GERP RS
5.5
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
Splicevardb
3.0
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AL_spliceai
1.0
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs397508201; hg19: chr7-117199516; API