7-117559594-T-G

Variant names:

• chr7-117559594-T-G
• rs74571530
• NM_000492.4:c.1523T>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PP2 PP3 BP4 BS2

The NM_000492.4(CFTR):​c.1523T>G​(p.Phe508Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00131 in 1,609,472 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F508L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00091 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (1 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:7 B:9
• Conservation: PhyloP100: 7.54
• Publications: 66 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 19 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.28578582).
• BS2: High Homozygotes in GnomAd4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1523T>G	p.Phe508Cys	missense	Exon 11 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.221+1139A>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1523T>G	p.Phe508Cys	missense	Exon 11 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1523T>G	p.Phe508Cys	missense	Exon 11 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.1433T>G	p.Phe478Cys	missense	Exon 10 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.000915 AC: 137 AN: 149752 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000396

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.000937 AC: 232 AN: 247712 AF XY: 0.000903

Gnomad AFR exome AF: 0.000495

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000326

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.00135 AC: 1965 AN: 1459602 Hom.: 1 Cov.: 30 AF XY: 0.00126 AC XY: 912 AN XY: 726240

African (AFR) AF: 0.000239 AC: 8 AN: 33448

American (AMR) AF: 0.000514 AC: 23 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.000281 AC: 15 AN: 53304

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00167 AC: 1851 AN: 1110114

Other (OTH) AF: 0.00111 AC: 67 AN: 60318

GnomAD4 genome AF: 0.000914 AC: 137 AN: 149870 Hom.: 2 Cov.: 32 AF XY: 0.000791 AC XY: 58 AN XY: 73370

African (AFR) AF: 0.000314 AC: 13 AN: 41360

American (AMR) AF: 0.000395 AC: 6 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00173 AC: 114 AN: 66050

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.00125 Hom.: 5

Bravo AF: 0.000880

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000951 AC: 115

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:7 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:2 Benign:4

Oct 01, 1990

OMIM

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

Oct 30, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F508C variant (also known as c.1523T>G), located in coding exon 11 of the CFTR gene, results from a T to G substitution at nucleotide position 1523. The phenylalanine at codon 508 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was first detected in two healthy individuals who also carried the p.F508del mutation on the other chromosome; thus, the authors suggested a benign classification (Kobayashi K et al. Am. J. Hum. Genet., 1990 Oct;47:611-5). Subsequently, p.F508C was detected with another pathogenic mutation in 3 of 182 individuals with congenital bilateral absence of the vas deferens (CBAVD). This same study also described 5 individuals who were compound heterozygous with another pathogenic mutation in a cohort of 5938 individuals suspected to have CF. However, the frequency of the p.F508C variant in this suspected CF population did not significantly differ from that of their control population (Havasi V et al. Genet. Med., 2008 Dec;10:910-4). Functional studies determined that this substitution does not affect CFTR function, protein folding, or the transport of the protein to the cell membrane, but could affect ion channel function, particularly when co-occurring with another alteration (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077; Du K et al. Nat. Struct. Mol. Biol., 2005 Jan;12:17-25; Cui L et al. J. Physiol. (Lond.), 2006 Apr;572:347-58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, this variant is unlikely to be causative of classic CF; however, its contribution to the development of a CFTR-related disorder is uncertain. Based on the available evidence, the clinical significance of this variant remains unclear.

Oct 02, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Uncertain:1 Benign:3

Apr 14, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 25, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Benign by Emory. Compund heterozygotes foe this variant and %508del variant were clinically normal, therefore this variant has been classified as benign by Kobayashi et al 1990. Frequency of the variant was higher in individuals with CBAVD (Havasi 2008). Phenotype does not meet reporting criteria.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR-related disorder Pathogenic:1 Uncertain:2

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Oct 02, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

not provided Pathogenic:1 Benign:1

Sep 08, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM3:Very Strong, PM2:Supporting, PP3

Hereditary pancreatitis Uncertain:1 Benign:1

Oct 21, 2020

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Apr 20, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PP3 supporting

Obstructive azoospermia Pathogenic:1

Aug 23, 2021

Institute of Reproductive Genetics, University of Münster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Sep 30, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1523T>G; p.Phe508Cys variant (rs74571530) is reported in the literature in individuals affected with monosymptomatic CFTR-related disorders (CFTR-RD), such as congenital bilateral absence of the vas deferens or pancreatitis, who also carried an additional pathogenic variant on the opposite chromosome (Dork 1997, Havasi 2008, Meschede 1993, Palermo 2016). This variant has also been reported in asymptomatic individuals (Desgeorges 1994, Kobayashi 1990, Macek 1992), although this may be due to reduced penetrance of CFTR-RD. Additionally, internal patient data indicate an increased association of this variant with CFTR-RD, but this variant is not associated with cystic fibrosis. In one study, p.Phe508Cys is suggested to be a modifier of S1251N severity when found in cis (Cuyx 2022). The p.Phe508Cys variant is also reported in ClinVar (Variation ID: 7126). It is observed in the non-Finnish European population with an allele frequency of 0.18% (230/125858 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.865). Based on available information, this variant is not causative for classic cystic fibrosis, but is considered likely pathogenic for CFTR-RD. References: Cuyx S et al. Severity of the S1251N allele in cystic fibrosis is affected by the presence of the F508C variant in cis. J Cyst Fibros. 2022 Jul;21(4):644-651. PMID: 35690578. Desgeorges M et al. A healthy male with compound and double heterozygosities for delta F508, F508C, and M47OV in exon 10 of the cystic fibrosis gene. Am J Hum Genet. 1994 54(2):384-5. PMID: 7508183. Dork T et al. Distinct spectrum of CFTR gene mutations in congenital absence of vas deferens. Hum Genet. 1997 100(3-4):365-77. PMID: 9272157. Havasi V et al. The role of the F508C mutation in congenital bilateral absence of the vas deferens. Genet Med. 2008 10(12):910-4. PMID: 19092444. Kobayashi K et al. Benign missense variations in the cystic fibrosis gene. Am J Hum Genet. 1990 47(4):611-5. PMID: 1977306. Macek M Jr et al. Missense variations in the cystic fibrosis gene: heteroduplex formation in the F508C mutation. Am J Hum Genet. 1992 Nov;51(5):1173-4. PMID: 1384326. Meschede D et al. Compound heterozygosity for the delta F508 and F508C cystic fibrosis transmembrane conductance regulator (CFTR) mutations in a patient with congenital bilateral aplasia of the vas deferens. Am J Hum Genet. 1993 Jul;53(1):292-3. PMID: 7686336. Palermo JJ et al. Genophenotypic Analysis of Pediatric Patients With Acute Recurrent and Chronic Pancreatitis. Pancreas. 2016 Oct;45(9):1347-52. PMID: 27171515.

Infertility disorder Uncertain:1

MAGI's Lab - Research, MAGI Group

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.5
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.96
MVP		1.0
MPC		0.013
ClinPred		0.083	T
GERP RS		5.5
Varity_R		0.94
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs74571530; hg19: chr7-117199648; COSMIC: COSV107197671;