7-117606695-C-T

Position:

chr7-117606695-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_ModeratePP5_Strong

The NM_000492.4(CFTR):c.2930C>T(p.Ser977Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000567 in 1,587,422 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S977P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:10O:2

Conservation

PhyloP100: 7.30

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117606694-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53599.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.915

PP5

Variant 7-117606695-C-T is Pathogenic according to our data. Variant chr7-117606695-C-T is described in ClinVar as [drug_response]. Clinvar id is 53601.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {drug_response=1, not_provided=1, Likely_pathogenic=2, Pathogenic=7}. Variant chr7-117606695-C-T is described in Lovd as [Pathogenic]. Variant chr7-117606695-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2930C>T	p.Ser977Phe	missense_variant	18/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2930C>T	p.Ser977Phe	missense_variant	18/27	1	NM_000492.4	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.178-1706G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151906

Hom.:

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251114

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000557

AC:

AN:

1435516

Hom.:

Cov.:

AF XY:

0.00000698

AC XY:

AN XY:

716198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000551

Gnomad4 OTH exome

AF:

0.0000336

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151906

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74178

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000490

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

Significance: drug response

Submissions summary: Pathogenic:10Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:4Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 24, 2023	Variant summary: CFTR c.2930C>T (p.Ser977Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251218 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2930C>T has been reported in the literature as a variant of varying clinical consequence due to reports of its presence in individuals affected with Non-classic Cystic Fibrosis, CBAVD, ICP, and classic CF (example, Bareil_2007, Claustres_2000, Goubau_2009, Lakeman_2008, Loumi_2008, Ratbi_2007, Scotet_2003, Sermet-Gaudelus_2010, Sofia_2016, Sorio_2013, Sosnay_2013, Terlizzi_2016, Tzetis_2001, Sasaki_2020, Sawicki_2022). At least five of these patients were found to also harbor the F508del variant (e.g., Sermet-Gaudelus_2010, Sawicki_2022). Additionally, in some of these reports the variant was reported in cis with the 5T allele (example, Bareil_2007, Sorio_2013, Terlizzi_2016). These data indicate that the variant is very likely to be associated with disease. Several publications report experimental evidence finding that the variant results in a defect in protein function (e.g., Van Goor_2014, Bihler_2023 (no PMID)). The most pronounced variant effect results in decreased chloride ion transport (5.5% of wild-type) and decreased CFTR maturation (37% of wild-type) in a Fischer rat thyroid (FRT) cell system (Van Goor_2014). The following publications have been ascertained in the context of this evaluation (PMID: 17975025, 10923036, 26014425, 19318346, 18373402, 17572159, 25910067, 32934006, 25735457, 17329263, 12815607, 20538955, 27264265, 23361109, 23974870, 27738188, 11354633, 23891399, 32483343, 36319933). Six submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n = 4) or likely pathogenic (n = 2). Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 01, 2023	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 977 of the CFTR protein (p.Ser977Phe). This variant is present in population databases (rs141033578, gnomAD 0.01%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 19318346, 23361109). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53601). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2019	The p.S977F pathogenic mutation (also known as c.2930C>T), located in coding exon 18 of the CFTR gene, results from a C to T substitution at nucleotide position 2930. The serine at codon 977 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. This alteration has been reported as a variant of varying clinical consequences (VVCC) (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; The Clinical and Functional TRanslation of CFTR (CFTR2); available at http://cftr2.org. Accessed January 11, 2019). It has been reported in cis with (TG)12-5T and in trans with a second CFTR alteration in individuals with varying clinical phenotypes including cystic fibrosis, congenital bilateral absences of the vas deferens (CBAVD), other CFTR-related disorders, and an asymptomatic carrier (Claustres M et al. Hum. Mutat., 2017 10;38:1297-1315). In one study, this mutation was confirmed in cis with (TG)12-5T and in trans with p.F508del in a male with azoospermia, bilateral bronchiectasis, acute pancreatitis, recurrent lung infections, sweat chloride levels of 40 and 42 mmol/L, and normal lung function (Sorio C et al. J. Cyst. Fibros., 2013 Dec;12:821-5). In FRT cells, levels of mature CFTR protein and chloride transport were reduced compared to wild type (Van Goor F et al. J. Cyst. Fibros., 2014 Jan;13:29-36). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jun 27, 2019	- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Cystic fibrosis;na:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Hereditary pancreatitis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 04, 2022

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 27, 2021

The CFTR c.2930C>T, p.Ser977Phe variant (rs141033578) has been reported in patients diagnosed with cystic fibrosis (Le Marechal 2001, Loumi 2008, Scotet 2003, Lakeman 2008) and CFTR-related disorders (Bareil 2007, Goubau 2009, Lebecque 2002, Ratbi 2007, Sermet-Gaudelus 2010, Sorio 2013, Trujillano 2013, Tzetis 2001). It was identified in-cis with the pathogenic 12TG-5T variant in multiple individuals (Lebecque 2002, Sorio 2013, Trujillano 2013, Tzetis 2001); therefore, it is possible that p.Ser977Phe and 12TG-5T could represent a complex allele if found together. Functional characterization of the p.Ser977Phe variant indicates wildtype levels of CFTR expression and protein maturation, but the variant protein has a chloride transport activity at 5 percent of wildtype CFTR (Van Goor 2014, CFTR2 database). The variant is listed in ClinVar (Variation ID: 53601), and found in the general population with an overall allele frequency of 0.001% (3/251114 alleles) in the Genome Aggregation Database. The serine at codon 977 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.906). Due to the variability of associated clinical phenotype, the p.Ser977Phe variant is considered to be likely pathogenic with varying clinical consequences. References: CFTR2 database: http://cftr2.org/ Bareil C et al. Comprehensive and rapid genotyping of mutations and haplotypes in congenital bilateral absence of the vas deferens and other cystic fibrosis transmembrane conductance regulator-related disorders. J Mol Diagn. 2007 Nov;9(5):582-8. PMID: 17975025. Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91. PMID: 19318346. Lakeman P et al. CFTR mutations in Turkish and North African cystic fibrosis patients in Europe: implications for screening. Genet Test. 2008 Mar;12(1):25-35. PMID: 18373402. Le Marechal C et al. Complete and rapid scanning of the cystic fibrosis transmembrane conductance regulator (CFTR) gene by denaturing high-performance liquid chromatography (D-HPLC): major implications for genetic counselling. Hum Genet. 2001; 108(4):290-8. PMID: 11379874. Lebecque P et al. Mutations of the cystic fibrosis gene and intermediate sweat chloride levels in children. Am J Respir Crit Care Med. 2002; 165(6):757-61. PMID: 11897640. Loumi O et al. CFTR mutations in the Algerian population. J Cyst Fibros. 2008 Jan;7(1):54-9. PMID: 17572159. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007; 22(5):1285-91. PMID: 17329263. Scotet V et al. Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland. Hum Mutat. 2003 Jul;22(1):105. PMID: 12815607. Sermet-Gaudelus I et al. Clinical phenotype and genotype of children with borderline sweat test and abnormal nasal epithelial chloride transport. Am J Respir Crit Care Med. 2010 Oct 1;182(7):929-36. PMID: 20538955. Sorio C et al. Impaired CFTR function in mild cystic fibrosis associated with the S977F/T5TG12complex allele in trans with F508del mutation. J Cyst Fibros. 2013; 12(6):821-5. PMID: 23361109. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013; 45(10):1160-7. PMID: 23974870 Trujillano D et al. Next generation diagnostics of cystic fibrosis and CFTR-related disorders by targeted multiplex high-coverage resequencing of CFTR. J Med Genet. 2013; 50(7):455-62. PMID: 23687349. Tzetis M et al. CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Ge -

CFTR-related disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 27, 2019

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 16, 2024

- -

ivacaftor response - Efficacy

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.;.;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.91

D;D;D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.1

H;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-3.8

D;.;.;D;.

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;.;.;D;.

Polyphen

0.75

P;.;.;.;.

Vest4

0.88

MVP

1.0

MPC

0.016

ClinPred

1.0

GERP RS

5.4

Varity_R

0.96

gMVP

0.98

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over