7-117587737-A-T

Variant names:

• chr7-117587737-A-T
• rs397508233
• NM_000492.4:c.1585-2A>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1585-2A>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,132 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 8.22
• 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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02138195 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.6, offset of -48, new splice context is: gatgtgcctttcaaattcAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117587737-A-T is Pathogenic according to our data. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117587737-A-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 1027585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1585-2A>T		splice_acceptor_variant, intron_variant	Intron 11 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1585-2A>T		splice_acceptor_variant, intron_variant	Intron 11 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1431132 Hom.: 0 Cov.: 26 AF XY: 0.00000140 AC XY: 1 AN XY: 714046

African (AFR) AF: 0.00 AC: 0 AN: 32790

American (AMR) AF: 0.00 AC: 0 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25924

East Asian (EAS) AF: 0.00 AC: 0 AN: 39498

South Asian (SAS) AF: 0.00 AC: 0 AN: 85644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084292

Other (OTH) AF: 0.0000168 AC: 1 AN: 59360

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:4

Nov 09, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1585-2A>T intronic variant results from an A to T substitution two nucleotides upstream from coding exon 12 in the CFTR gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, based on available data in the literature, the in-frame transcript is unlikely to occur. In one minigene expression assay, 5 different variants were tested at this acceptor site, and none of them resulted in the in-frame transcript (Sharma N. et al. Hum Mutat 2014 Oct;35(10):1249-59). Another study found that a different alteration at this position, c.1585-2A>G, resulted in skipping of exon 12 and retention of 6 nucleotides in intron 11 (both out-of-frame transcripts). The presence of these two transcripts was confirmed in total RNA obtained from a patient with c.1585-2A>G (Silva IAL et al. Biochim Biophys Acta Mol Basis Dis 2020 11;1866(11):165905). In the same minigene assay, a common mutation c.1585-1G>A (1717-1G>A), resulted in skipping of exon 12 and a deletion of 1 nucleotide in exon 12. Further, analysis of RNA from nasal epithelial cells revealed that c.1585-1G>A resulted in skipping of exon 12 in 3 patients (Hull J. et al. Hum Mol Genet 1993 Jun;2(6):689-92). The c.1585-2A>T variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD).This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Jan 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 11 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with cystic fibrosis (PMID: 11788090). ClinVar contains an entry for this variant (Variation ID: 1027585). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25066652). For these reasons, this variant has been classified as Pathogenic. -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The splice site c.1585-2A>T variant in CFTR gene has been reported in ClinVar as Likely Pathogenic. The c.1585-2A>T variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Likely Pathogenic. -

May 08, 2025

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.1585-2A>T 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of CFTR function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250846 control chromosomes. c.1585-2A>T has been observed in individual(s) affected with Cystic Fibrosis (example: Beauchamp_2019). The following publication has been ascertained in the context of this evaluation (PMID: 31036917). ClinVar contains an entry for this variant (Variation ID: 1027585). Based on the evidence outlined above, the variant was classified as pathogenic. -

CFTR-related disorder Pathogenic:1

Aug 28, 2017

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 26, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		8.2
GERP RS		5.1
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.30		Position offset: 14
DS_AL_spliceai		0.97		Position offset: 2

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

Other links and lift over

dbSNP: rs397508233; hg19: chr7-117227791;