rs121908759

Positions:

chr7-117592032-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3PP5

The NM_000492.4(CFTR):c.1865G>A(p.Gly622Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,603,502 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 2 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:21U:1B:1

Conservation

PhyloP100: 9.23

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 Uncertain_significance. Variant got 4 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.764

PP5

Variant 7-117592032-G-A is Pathogenic according to our data. Variant chr7-117592032-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35833.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=8, Benign=1, Uncertain_significance=1, Pathogenic=10}. Variant chr7-117592032-G-A is described in Lovd as [Pathogenic]. Variant chr7-117592032-G-A is described in Lovd as [Likely_pathogenic]. Variant chr7-117592032-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1865G>A	p.Gly622Asp	missense_variant	14/27	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.1865G>A	p.Gly622Asp	missense_variant	14/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000103

AC:

AN:

242874

Hom.:

AF XY:

0.0000762

AC XY:

AN XY:

131156

show subpopulations

Gnomad AFR exome

AF:

0.000752

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000611

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000341

GnomAD4 exome

AF:

0.0000937

AC:

136

AN:

1451302

Hom.:

Cov.:

AF XY:

0.0000832

AC XY:

AN XY:

721128

show subpopulations

Gnomad4 AFR exome

AF:

0.000458

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000530

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00165

GnomAD4 genome

AF:

0.000368

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000772

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000308

Hom.:

Bravo

AF:

0.000461

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:21Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6Uncertain:1Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 07, 2015	The p.Gly622Asp variant in CFTR has been reported in 8 compound heterozygous ind ividuals with CFTR-related disorders who had a pathogenic variant on the second allele (Marion 2014). Four of these individuals had classic cystic fibrosis, whe reas the other four had azoospermia or oligospermia only. In vitro functional st udies provide some evidence that the p.Gly622Asp variant may impact protein func tion (Norez 2008, Billet 2010), although these types of assays may not accuratel y represent biological function. This variant has also been identified in 9/9888 of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs121908759). While this variant has been identified in the general population, its frequency is consistent with a recessive carrier fr equency. Computational prediction tools and conservation analysis also suggest t hat the p.Gly622Asp variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly622 Asp variant is likely pathogenic for CFTR-related disorders with the phenotypic spectrum ranging from male infertility to classic cystic fibrosis. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Nov 22, 2019	CFTR variant associated with variable clinical consequences. See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The CFTR c.1865G>A (p.Gly622Asp) missense variant was reported in a total of 22 patients including 11 in a compound heterozygous state (five of whom carried one of two well-established pathogenic variants p.Phe508del or p.Tyr122Ter as the second variant), and ten in a heterozygous state with clinical presentations including classic cystic fibrosis (CF) with and without pancreatic sufficiency, male infertility, and fetal echogenic bowel and one in a heterozygous state with oligospermia (Vankeerberghen et al. 1998; Marion et al. 2015). Additionally, the p.Gly622Asp variant is found in a compound heterozygous state in a patient who at four years old was reportedly without any clinical signs of CF but who could manifest symptoms at a later age (Oca et al. 2009). The p.Gly622Asp variant was absent from 400 controls but was identified in three of 412 healthy individuals in a heterozygous state (Masson et al. 2013). The variant is reported at a frequency of 0.00091 in the African population of the Exome Aggregation Consortium database. Functional studies in COS1, COS7 and HEK 293 cells demonstrated that the p.Gly622Asp variant resulted in abnormal intracellular trafficking and reduced CFTR activity (Vankeerberghen et al. 1998; Norez et al. 2008; Billet et al. 2010). Based on the collective evidence, the p.Gly622Asp variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 24, 2024	The p.G622D variant (also known as c.1865G>A), located in coding exon 14 of the CFTR gene, results from a G to A substitution at nucleotide position 1865. The glycine at codon 622 is replaced by aspartic acid, an amino acid with similar properties. This variant was identified in a child with cystic fibrosis (CF) in conjunction with p.Y122*, but was also identified in an asymptomatic 4 year old in conjunction with p.F508del; however, phase was not provided for either child (Munck A et al. J. Pediatr., 2009 Dec;155:928-930.e1; Oca F et al. Clin. Chem., 2009 Dec;55:2214-7). In a cohort of individuals with classic CF, this variant was identified in four pancreatic insufficient individuals with elevated sweat chloride levels and pulmonary infections in conjunction with a severe CF mutation; however, the phase was not confirmed. In the same study, this variant was seen in eight infertile males in conjunction with a second CFTR alteration (Marion H et al. J. Cyst. Fibros., 2015 May;14:305-9). Functional studies have demonstrated that this alteration results in lower intrinsic chloride channel activities, altered protein trafficking, reduced levels of fully mature CFTR protein, and reduced chloride conductance compared to wild type (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9; Norez C et al. J. Pharmacol. Exp. Ther., 2008 Apr;325:89-99; Billet A et al. J. Biol. Chem., 2010 Jul;285:22132-40; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077; Han ST et al. JCI Insight, 2018 Jul;3:). However, this variant retains almost 20% of normal CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077), and as a result, it is considered variant of varying clinical consequence by The Clinical and Functional TRanslation of CFTR (CFTR2) (available at http://cftr2.org. Accessed September 20, 2019). 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 the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 03, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Mar 30, 2023	This sequence change is predicted to replace glycine with aspartic acid at codon 622 of the CFTR protein, p.(Gly622Asp). The glycine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the ABC transporter 1 domain. There is a moderate physicochemical difference between glycine and aspartic acid. The variant is present in a large population cohort at a frequency of 0.01%, which is consistent with a recessive disorder (rs121908759, 34/274,254 alleles, 0 homozygotes in gnomAD v2.1). The variant has been identified compound heterozygous with a second pathogenic allele in multiple cases diagnosed with cystic fibrosis and other CFTR-related disorders (PMID: 25443471). Moderately reduced protein function has been shown with stable expression of the variant in a human airway cell line, and significantly lower intrinsic chloride channel activities in in vitro assays in COS1 cells (PMID: 9736778, 29805046). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as PATHOGENIC. Following criteria are met: PM3_VeryStrong, PM2, PS3_Supporting, PP3. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, flagged submission	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2023	Classified as a variant of varying clinical consequence in a well-curated database (CFTR2); Published functional studies are conflicting: normal or reduced protein maturation, reduced chloride transport activity, and reduced protein function (Vankeerberghen 1998, Norez 2008, Billet 2010, Han 2018, Raraigh 2018); Observed in the heterozygous state in an individual with asthma and borderline sweat chloride levels, an individual with oligospermia, an individual with congenital absence of vas deferens, and also in multiple healthy individuals (Vankeerberghen 1998, Monaghan 2004, Luo 2021); Observed in individuals with pancreatitis referred for genetic testing at GeneDx; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29174009, 34996830, 18230692, 9736778, 20435887, 19833837, 22975760, 25489051, 23951356, 15354332, 29805046, 30046002, 30609409, 30032850, 17329263, 25443471, 28603918, 16596947, 31589614, 32777524, 35313924, 34804071, 35314707) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 02, 2021	The CFTR c.1865G>A; p.Gly622Asp variant (rs121908759) is reported in the compound heterozygous state in multiple individuals with symptoms ranging from classic cystic fibrosis to CFTR-related disorders, such as male infertility and pancreatitis (Ceyhan-Birsoy 2019, Masson 2013, Marion 2015, Ratbi 2007, Vankeerberghen 1998). This variant is also reported in ClinVar (Variation ID: 35833), and is observed in the general population with an overall allele frequency of 0.012% (34/274254 alleles) in the Genome Aggregation Database. The glycine at residue 622 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.964). Functional characterization of the variant protein indicates a defect in CFTR processing and maturation, leading to a reduced chloride transport activity (Billet 2010, Raraigh 2018, Vankeerberghen 1998). Based on the above information, the variant is classified as pathogenic with varying clinical consequences. References: Billet A et al. C terminus of nucleotide binding domain 1 contains critical features for cystic fibrosis transmembrane conductance regulator trafficking and activation. J Biol Chem. 2010 285(29):22132-40. Ceyhan-Birsoy O et al. Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Am J Hum Genet. 2019 Jan 3;104(1):76-93. Marion H et al. The p.Gly622Asp (G622D) mutation, frequently found in Reunion Island and in black populations, is associated with a wide spectrum of CF and CFTR-RD phenotypes. J Cyst Fibros. 2015 14(3):305-9. 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. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. 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. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 7(11):1761-9. -
Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jan 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 03, 2021	This variant is associated with a variable phenotype and individuals with this variant and a CFTR pathogenic variant associated with classic CF may be affected by a CFTR-related disorder, such as oligospermia, CBAVD, or pancreatic-sufficient CF (PMIDs: 17329263 (2007), 23951356 (2013), 25443471 (2015)). Several functional studies have reported that this variant affects proper CFTR function (PMID 20435887 (2010), 18230692 (2008), 9736778 (1998), 30046002 (2018)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2021	- -

CFTR-related disorder

Pathogenic:2

Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Dec 25, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 21, 2024	The CFTR c.1865G>A variant is predicted to result in the amino acid substitution p.Gly622Asp. This variant has been reported to be pathogenic for cystic fibrosis and CFTR-related disease (see for example Vankeerberghen et al. 1998. PubMed ID: 9736778; Marion et al. 2015. PubMed ID: 25443471; http://www.genet.sickkids.on.ca/). Experimental studies indicate this variant impacts protein function (Norez et al. 2008. PubMed ID: 18230692). This variant is reported in 0.085% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. -

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 -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

- -

Hereditary pancreatitis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

Apr 12, 2021

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 30, 2024

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.;D;.

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.9

H;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.9

D;.;D;.

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0040

D;.;D;.

Sift4G

Uncertain

0.0020

D;.;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.97

MVP

1.0

MPC

0.015

ClinPred

0.57

GERP RS

5.5

Varity_R

0.95

gMVP

0.96

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