rs201716473

Variant names:

• chr7-117602800-A-G
• rs201716473
• NM_000492.4:c.2620-26A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS2_Supporting

The NM_000492.4(CFTR):​c.2620-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,612,290 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (14 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Uncertain significance reviewed by expert panel P:1 U:5 B:10
• Conservation: PhyloP100: 1.54
• Publications: 5 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS2: High Homozygotes in GnomAdExome4 at 14 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2620-26A>G		intron_variant	Intron 15 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2620-26A>G		intron_variant	Intron 15 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 152180 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00161 AC: 405 AN: 251450 AF XY: 0.00152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.0264

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000323

Gnomad NFE exome AF: 0.000967

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00138 AC: 2013 AN: 1459992 Hom.: 14 Cov.: 30 AF XY: 0.00132 AC XY: 962 AN XY: 726468

African (AFR) AF: 0.000179 AC: 6 AN: 33436

American (AMR) AF: 0.0000895 AC: 4 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0255 AC: 666 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86214

European-Finnish (FIN) AF: 0.000374 AC: 20 AN: 53412

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00104 AC: 1151 AN: 1110350

Other (OTH) AF: 0.00260 AC: 157 AN: 60324

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152298 Hom.: 1 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74470

African (AFR) AF: 0.000120 AC: 5 AN: 41580

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00100 AC: 68 AN: 68010

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00425 Hom.: 0

Bravo AF: 0.00121

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5 Benign:10

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Uncertain:1 Benign:7

Feb 13, 2018

Counsyl

Significance: Likely benign

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. -

Jun 14, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Feb 10, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 17, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2018

CFTR2

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: research

- -

Mar 26, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither -

-

Baylor Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:3 Benign:1

Dec 24, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 06, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2620-26A>G variant (rs201716473), also known as 2752-26A>G, is reported in the literature in individuals with monosymptomatic atypical cystic fibrosis (i.e. congenital bilateral absence of the vas deferens, pancreatitis) and normal to borderline sweat chloride values (Alonso 2007, Danziger 2004, Dequeker 2009, Pall 2007, Tzetis 1997, Yadav 2015). This variant is reported in ClinVar (Variation ID: 53529), and is found in the Ashkenazi Jewish population with an allele frequency of 2.7% (277/10,368 alleles, including 3 homozygotes) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant does not alter splicing. Functional analyses of the variant transcript show that this variant does not affect normal splicing (Bergougnoux 2015, Giorgi 2015). While the population frequency suggests that this variant is unlikely to be associated with classic CF, its association with milder phenotypes cannot be ruled out. Thus, due to conflicting information, the clinical significance of the c.2620-26A>G variant is uncertain at this time. References: Alonso MJ et al. Spectrum of mutations in the CFTR gene in cystic fibrosis patients of Spanish ancestry. Ann Hum Genet. 2007; 71(Pt 2):194-201. PMID: 17331079. Bergougnoux A et al. Should diffuse bronchiectasis still be considered a CFTR-related disorder? J Cyst Fibros. 2015; 14(5):646-53. PMID: 25797027. Danziger KL et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004; 19(3):540-6. PMID: 14998948. Dequeker E et al. Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders--updated European recommendations. Eur J Hum Genet. 2009; 17(1):51-65. PMID: 18685558. Giorgi G et al. Validation of CFTR intronic variants identified during cystic fibrosis population screening by a minigene splicing assay. Clin Chem Lab Med. 2015; 53(11):1719-23. PMID: 25781545. Pall H et al. Primary sclerosing cholangitis in childhood is associated with abnormalities in cystic fibrosis-mediated chloride channel function. J Pediatr. 2007; 151(3):255-9. PMID: 17719933. Tzetis M et al. Characterization of more than 85% of cystic fibrosis alleles in the Greek population, including five novel mutations. Hum Genet. 1997; 99(1):121-5. PMID: 9003508. Yadav H et al. Chronic cough with normal sweat chloride: Phenotypic descriptions of two rare cystic fibrosis genotypes. Respir Med Case Rep. 2015; 17:17-9. PMID: 27222777. -

Apr 07, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.2620-26A>G variant (alternatively also known as 2752-26A>G) involves the alteration of a non-conserved intronic nucleotide. Mutation taster predicts a benign outcome for this variant. 1/5 splice prediction tools predict a creation of new splice acceptor site, however, 5/5 tools predict no significant effect in utilization of the consensus splice acceptor site. Two functional studies show that this variant does not affect normal splicing (Bergougnoux_2015, Giorgi_2015). This variant was found in 145/121484 control chromosomes from ExAC (including one homozygote) at a frequency of 0.0011936, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant of interest has been reported in multiple CF patients without strong evidence for causality (i.e. cosegregation with disease and/or concordant recessive genotype). Meanwhile the patients were not comprehensively tested, therefore a possibility of missing a real pathogenic mutation in same allele as well as its co-occurrence in other allele (in trans) with another pathogenic variant cannot be completely ruled out. One adult patient confirmed to have a mild pathogenic variant in other allele (5T allele in intron 9) had milder clinical features of CF (chronic cough, nasal congestion and postnasal drip present for 3 years) with sweat chloride level <30 mmol/L (Yadav_2016). Pulmonary function testing and fecal elastase level in the patient were within normal limits and chest X-ray and CT of the sinuses were also normal. This variant has also been reported in patients with pulmonary and GI manifestations (such as primary sclerosing cholangitis, inflammatory bowel disease, and diffuse bronchiectasis). A new database gnomAD (which comprises data from ExAC plus individuals undergoing genome sequencing) reports the variants allele frequency in Ashkenazi Jewish at 2.640% (268/10150 chromosomes) including 3 homozygotes, which is an evidence against pathogenicity. In addition, one clinical diagnostic laboratory in ClinVar has classified this variant as likely benign. The variant was classified as polymorphism by a recent publication Bergougnoux_2015 in Journal of Cystic Fibrosis (PMID: 25797027), however is considered to have varying phenotypic consequence by CFTR2 database. Taken together, this variant is classified as VUS-possibly benign. -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Uncertain:1

May 20, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Benign:1

Dec 20, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pancreatitis Benign:1

Dec 08, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.62
PhyloP100		1.5
Mutation Taster		=100/0	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201716473; hg19: chr7-117242854;