rs201716473

Positions:

• chr7-117602800-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6_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:9
• Conservation: PhyloP100: 1.54

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-117602800-A-G is Benign according to our data. Variant chr7-117602800-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 53529.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=4, Pathogenic=1, Benign=2}.
• BS2: High Homozygotes in GnomAdExome4 at 14 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/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2620-26A>G		intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2620-26A>G		intron_variant		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

GnomAD3 exomes AF: 0.00161 AC: 405 AN: 251450 Hom.: 3 AF XY: 0.00152 AC XY: 207 AN XY: 135892

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.0255

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.000374

Gnomad4 NFE exome AF: 0.00104

Gnomad4 OTH exome AF: 0.00260

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

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.0248

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00425 Hom.: 0

Bravo AF: 0.00121

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:5 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Uncertain:1 Benign:6

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 24, 2019	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Mar 26, 2018	the variant does not result in CFTR-RD neither -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 10, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Feb 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Uncertain significance, reviewed by expert panel	research	CFTR2	Aug 31, 2018	- -

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 24, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 04, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 06, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2017	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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

CFTR-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2019

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 20, 2017

- -

Hereditary pancreatitis Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 08, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.7
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs201716473; hg19: chr7-117242854;