rs1800076
Positions:
Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2
The NM_000492.4(CFTR):c.224G>A(p.Arg75Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0301 in 1,611,610 control chromosomes in the GnomAD database, including 1,043 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.019 ( 44 hom., cov: 33)
Exomes 𝑓: 0.031 ( 999 hom. )
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
7
6
5
Clinical Significance
Conservation
PhyloP100: 7.71
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
PM1
In a helix (size 27) in uniprot entity CFTR_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000492.4
BP4
Computational evidence support a benign effect (MetaRNN=0.011586249).
BP6
Variant 7-117509093-G-A is Benign according to our data. Variant chr7-117509093-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35839.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Benign=6, not_provided=2, Uncertain_significance=3}. Variant chr7-117509093-G-A is described in Lovd as [Benign]. Variant chr7-117509093-G-A is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0186 (2830/152290) while in subpopulation NFE AF= 0.0342 (2325/68014). AF 95% confidence interval is 0.033. There are 44 homozygotes in gnomad4. There are 1183 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 44 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.224G>A | p.Arg75Gln | missense_variant | 3/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.224G>A | p.Arg75Gln | missense_variant | 3/27 | 1 | NM_000492.4 | ENSP00000003084 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0186 AC: 2830AN: 152172Hom.: 44 Cov.: 33
GnomAD3 genomes
AF:
AC:
2830
AN:
152172
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0154 AC: 3874AN: 250966Hom.: 59 AF XY: 0.0153 AC XY: 2080AN XY: 135648
GnomAD3 exomes
AF:
AC:
3874
AN:
250966
Hom.:
AF XY:
AC XY:
2080
AN XY:
135648
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0313 AC: 45647AN: 1459320Hom.: 999 Cov.: 29 AF XY: 0.0299 AC XY: 21694AN XY: 726240
GnomAD4 exome
AF:
AC:
45647
AN:
1459320
Hom.:
Cov.:
29
AF XY:
AC XY:
21694
AN XY:
726240
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0186 AC: 2830AN: 152290Hom.: 44 Cov.: 33 AF XY: 0.0159 AC XY: 1183AN XY: 74466
GnomAD4 genome
AF:
AC:
2830
AN:
152290
Hom.:
Cov.:
33
AF XY:
AC XY:
1183
AN XY:
74466
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
131
ALSPAC
AF:
AC:
183
ESP6500AA
AF:
AC:
43
ESP6500EA
AF:
AC:
265
ExAC
AF:
AC:
1863
Asia WGS
AF:
AC:
11
AN:
3472
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:15Other:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cystic fibrosis Uncertain:2Benign:6
Benign, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 22, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 01, 2014 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 01, 2022 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 06, 2019 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
Benign, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | the variant does not result in CFTR-RD neither - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
not provided Uncertain:2Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 06, 2023 | The CFTR c.224G>A (p.Arg75Gln) variant has been reported in the published literature in individuals affected with pancreatitis (PMID: 25033378 (2014), 27555793 (2016), 32447501 (2021), 35096544 (2022)), chronic obstructive pulmonary disease (PMID: 15463907 (2004), 34996830 (2022)), rheumatoid arthritis and/or diffuse bronchiectasis (PMID: 21131649 (2011), 25797027 (2015)), and idiopathic infertility (PMID: 32155011 (2020)). Functional studies show the variant as having acceptable (PMID: 18306312 (2008), 25033378 (2014)) or reduced chloride conductance activity (PMID: 23974870 (2013), 35418593 (2022)), reduced mRNA expression and processing (PMID: 25797027 (2015)), and defects in bicarbonate conductance (PMID: 25033378 (2014)). However, other studies report the variant CFTR protein is processed and glycosylated in a manner comparable to the wild-type (PMID: 18306312 (2008), 23974870 (2013), 25033378 (2014), 35418593 (2022)). The frequency of this variant in the general population, 0.039 (1980/50646 chromosomes in North-Western European subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 07, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | CFTR: BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 28, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 02, 2023 | - - |
not specified Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 03, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 16, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 28, 2014 | - - |
CFTR-related disorder Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Feb 01, 2022 | - - |
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. - |
Hereditary pancreatitis Benign:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 18, 2021 | - - |
Lung disease, non-specific Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | May 14, 2015 | - - |
Abnormality of the pancreas Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as Uncertain significance and reported on 02-10-2019 by Lab or GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;.;T;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N;.
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D;.
Sift4G
Pathogenic
D;.;.;D;.
Polyphen
D;.;.;.;.
Vest4
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at