rs121909046

Positions:

chr7-117535318-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The ENST00000003084.11(CFTR):c.650A>G(p.Glu217Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,614,056 control chromosomes in the GnomAD database, including 67 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. E217Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0034 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 58 hom. )

Consequence

CFTR
ENST00000003084.11 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:13B:6

Conservation

PhyloP100: 8.84

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1

In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 177 pathogenic changes around while only 18 benign (91%) in ENST00000003084.11

BP4

Computational evidence support a benign effect (MetaRNN=0.008159667).

BP6

Variant 7-117535318-A-G is Benign according to our data. Variant chr7-117535318-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7238.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=11}. Variant chr7-117535318-A-G is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.650A>G	p.Glu217Gly	missense_variant	6/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.650A>G	p.Glu217Gly	missense_variant	6/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00339

AC:

516

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0104

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.0363

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000838

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00444

AC:

1117

AN:

251436

Hom.:

AF XY:

0.00406

AC XY:

552

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00952

Gnomad SAS exome

AF:

0.000817

Gnomad FIN exome

AF:

0.0348

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.00635

GnomAD4 exome

AF:

0.00193

AC:

2815

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00183

AC XY:

1333

AN XY:

727224

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0111

Gnomad4 SAS exome

AF:

0.000556

Gnomad4 FIN exome

AF:

0.0340

Gnomad4 NFE exome

AF:

0.000322

Gnomad4 OTH exome

AF:

0.00233

GnomAD4 genome

AF:

0.00338

AC:

515

AN:

152202

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

355

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0102

Gnomad4 SAS

AF:

0.00166

Gnomad4 FIN

AF:

0.0363

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.000601

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00392

AC:

476

Asia WGS

AF:

0.0150

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:13Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:6Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2023	The CFTR c.650A>G; p.Glu217Gly variant (rs121909046) is reported in the literature in patients affected with congenital bilateral absence of vas deferens (Cheng 2022, Fang 2022, Li 2012, Luo 2021), bronchiectasis (Guan 2018, Lee 2003), chronic pancreatitis (Masson 2013, Steiner 2011, Xiao 2017), or cystic fibrosis (Petrova 2020, Shen 2022). This variant is also reported in ClinVar database (Variation ID: 7238) and is found in the Finnish European population with an allele frequency of 3.5% (875/25118 alleles, including 25 homozygotes) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.546). However, functional analyses of the variant protein show reduced function in vitro (Hammerle 2001, Lee 2003). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Cheng H et al. Genetic analysis and intracytoplasmic sperm injection outcomes of Chinese patients with congenital bilateral absence of vas deferens. J Assist Reprod Genet. 2022 Mar;39(3):719-728. PMID: 35119551. Fang J et al. Congenital absence of the vas deferens with hypospadias or without hypospadias: Phenotypic findings and genetic considerations. Front Genet. 2022 Nov 9;13:1035468. PMID: 36437957. Guan et al. Next-generation sequencing for identifying genetic mutations in adults with bronchiectasis. J Thorac Dis. 2018 May;10(5):2618-2630. PMID: 29997923. Hammerle MM et al. Disease-associated mutations in the extracytoplasmic loops of cystic fibrosis transmembrane conductance regulator do not impede biosynthetic processing but impair chloride channel stability. J Biol Chem. 2001 May 4;276(18):14848-54. PMID: 11278813. Lee JH et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003 Sep 15;12(18):2321-32. PMID: 12952861. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 11(4):316-23. PMID: 22483971. Luo et al. Mutation analysis of the cystic fibrosis transmembrane conductance regulator gene in Chinese congenital absence of vas deferens patients. Gene. 2021 Jan 10;765:145045. PMID: 32777524. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. PMID: 23951356. Petrova NV et al. Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients. Genes (Basel). 2020 May 15;11(5):554. PMID: 32429104. Shen Y et al. Genetic spectrum of Chinese children with cystic fibrosis: comprehensive data analysis from the main referral centre in China. J Med Genet. 2022 Jul 20;60(3):310–5. PMID: 35858753. Steiner B et al . Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 32(8):912-20. PMID: 21520337. Xiao et al. Targeted Gene Next-Generation Sequencing in Chinese Children with Chronic Pancreatitis and Acute Recurrent Pancreatitis. J Pediatr. 2017 Dec;191:158-163.e3. PMID: 29173301. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CFTR: BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	Observed with CF-causing variants on the opposite allele (in trans) in asymptomatic individuals (Claustres et al., 2017); Observed in the homozygous state in healthy adult individuals tested at GeneDx and in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25087612, 23951356, 29058463, 34426522, 17516627, 21520337, 34405919, 29307731, 15463840, 11589722, 16126774, 11938439, 22664493, 26089335, 34996830, 16596947, 20558957, 17539902, 10922396, 22483971, 32777524, 32429104, 29173301, 24586523, 12952861, 27706244, 26436105, 20879059, 29997923, 18304229, 31916691, 11278813, 28603918, 31882543) -
Uncertain significance, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	May 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 13, 2023	BS1, BS2, PM3_strong, PS3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 10, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 04, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Cystic fibrosis

Pathogenic:1Uncertain:5Benign:2

Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 2 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_MOD, PM3, BS2, BP2 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 15, 2003	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 02, 2018	This alteration is classified as 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

CFTR-related disorder

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Apr 29, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 05, 2024

Variant summary: CFTR c.650A>G (p.Glu217Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0047 in 259928 control chromosomes, including 29 homozygotes (gnomAD and publications); particularly at a frequency of 0.0095 within the East Asian subpopulation in the gnomAD database. This frequency is approximately equal to the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing CFTR-related diseases phenotype (0.0095 vs 0.013), suggesting that the variant may be a benign polymorphism. c.650A>G has been reported in the literature in individuals affected with CFTR-Related Diseases such as Cystic Fibrosis (CF), chronic pancreatitis and CBAVD (example: Audrezet_2002, Guan_2018, Petrova_2020, Luo_2021), but also in many controls (example: Kars_2021). These reports do not provide unequivocal conclusions about association of the variant with CFTR-Related Diseases. Munck et al (2019) report a patient with inconclusive CF diagnosis harboring a second allele of F508del, with sweat chloride levels < 30 mmol/L. Nevertheless, Petroval et al (2020) report another patient with F508del in trans who had a diagnosis of CF, with sweat chloride levels of 63 mmol/L. CFTR-France database reports this variant in two asymptomatic compound heterozygotes with a CF-causing variant in trans. Functional studies report significantly decreased chloride channel activity associated with the variant when transfected into CHO-K1 and BHK cells (Hammerl_2001, Lee_2003, Chang_2018, Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 15463840, 11938439, 16596947, 38388235, 29307731, 17539902, 29997923, 11278813, 34426522, 20879059, 26089335, 31882543, 12952861, 22483971, 32777524, 22664493, 16126774, 31916691, 32429104, 31245908, 18304229, 21520337, 26436105, 11589722, 27706244, 31423445, 17516627, 24586523). ClinVar contains an entry for this variant (Variation ID: 7238). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;.;D;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D;D

MetaRNN

Benign

0.0082

T;T;T;T;T

MetaSVM

Uncertain

0.074

MutationAssessor

Benign

1.7

L;.;.;.;L

MutationTaster

Benign

1.0

A;A

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.0

N;.;.;N;.

REVEL

Uncertain

0.55

Sift

Uncertain

0.013

D;.;.;D;.

Sift4G

Uncertain

0.0050

D;.;.;D;.

Polyphen

0.053

B;.;.;.;.

Vest4

0.79

MVP

0.97

MPC

0.0038

ClinPred

0.065

GERP RS

5.5

Varity_R

0.54

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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