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

Variant names:

• chr7-117559462-A-G
• rs397508201
• NM_000492.4:c.1393-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_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: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 8.79
• Publications: 2 publications found

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)

ACMG classification

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
CFTR	NM_000492.4	c.1393-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 26	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1	n.221+1271T>C		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1393-2A>G		splice_acceptor_variant, intron_variant	Intron 10 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

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

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

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

Other links and lift over

dbSNP: rs397508201; hg19: chr7-117199516;