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GeneBe

rs113857788

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBS1_SupportingBS2

The NM_000492.4(CFTR):c.4056G>C(p.Gln1352His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000587 in 1,614,026 control chromosomes in the GnomAD database, including 18 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 nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.00060 ( 3 hom., cov: 33)
Exomes 𝑓: 0.00059 ( 15 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

7
9
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:10B:3

Conservation

PhyloP100: 2.15
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000492.4
BP4
Computational evidence support a benign effect (MetaRNN=0.015191972).
BS1
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000586 (857/1461710) while in subpopulation EAS AF= 0.0195 (773/39692). AF 95% confidence interval is 0.0183. There are 15 homozygotes in gnomad4_exome. There are 418 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFTRNM_000492.4 linkuse as main transcriptc.4056G>C p.Gln1352His missense_variant 25/27 ENST00000003084.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.4056G>C p.Gln1352His missense_variant 25/271 NM_000492.4 P2P13569-1

Frequencies

GnomAD3 genomes
AF:
0.000611
AC:
93
AN:
152198
Hom.:
3
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.0170
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000957
GnomAD3 exomes
AF:
0.00102
AC:
257
AN:
251226
Hom.:
3
AF XY:
0.000869
AC XY:
118
AN XY:
135760
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0134
Gnomad SAS exome
AF:
0.000196
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000489
GnomAD4 exome
AF:
0.000586
AC:
857
AN:
1461710
Hom.:
15
Cov.:
32
AF XY:
0.000575
AC XY:
418
AN XY:
727170
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0195
Gnomad4 SAS exome
AF:
0.000220
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00101
GnomAD4 genome
AF:
0.000597
AC:
91
AN:
152316
Hom.:
3
Cov.:
33
AF XY:
0.000712
AC XY:
53
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.0166
Gnomad4 SAS
AF:
0.000415
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000947
Alfa
AF:
0.000543
Hom.:
1
Bravo
AF:
0.000370
ExAC
AF:
0.000972
AC:
118

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:10Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Cystic fibrosis Pathogenic:1Uncertain:4Benign:2
Pathogenic, no assertion criteria providedliterature onlyOMIMSep 15, 2003- -
Uncertain significance, criteria provided, single submitterreference populationSoonchunhyang University Bucheon Hospital, Soonchunhyang University Medical CenterMar 18, 2016- -
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMay 12, 2021- -
Benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversitySep 07, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 01, 2023The p.Q1352H variant (also known as c.4056G>C), located in coding exon 25 of the CFTR gene, results from a G to C substitution at nucleotide position 4056. The glutamine at codon 1352 is replaced by histidine, an amino acid with highly similar properties. The variant has been reported in multiple Asian individuals with CFTR-related findings, including congenital absence of the vas deferens, chronic pancreatitis, and pulmonary disease cohorts; a few individuals were homozygotes and several had additional CFTR variants also detected (Dörk T et al. Hum. Genet., 1997 Sep;100:365-77; Anzai C et al. J. Cyst. Fibros., 2003 Mar;2:14-8; Lee JH et al. Hum. Mol. Genet., 2003 Sep;12:2321-32; Oka H et al. Intern Med, 2010 Jun;49:1251-2; Qiu L et al. Front Med, 2018 Oct;12:550-558; Iso M et al. Hum Genome Var, 2019 Apr;6:17; Yuan P et al. Andrology, 2019 05;7:329-340). In addition, in vitro functional studies showed that this variant results in a 70-80% reduction in the expression of the mature glycosylated CFTR protein and in chloride channel activity (Lee JH et al. Hum. Mol. Genet., 2003 Sep;12:2321-32). 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 cystic fibrosis; however, its contribution to the development of a CFTR-related disorder is uncertain. This alteration is thus classified as a variant of unknown significance. -
not provided Pathogenic:1Uncertain:4
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Nov 20, 2017- -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoApr 04, 2023The frequency of this variant in the general population, 0.018 (67/3806 chromosomes in Korean subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Although the variant has been identified in individuals described as having CF in the published literature (PMIDs: 16596947 (2005), 20558957 (2010), 31136843 (2019), 36409994 (2022)), this variant is likely not associated with classic CF, but it may be associated with CFTR-related diseases such as congenital bilateral absence of the vas deferens (CBAVD) (PMIDs: 28603918 (2017), 30811104 (2019), 32777524 (2021), 34673937 (2021), 35119551 (2022)), bronchiectasis (PMIDs: 12952861 (2003), 29997923 (2018)), and pancreatitis (PMIDs: 16187186 (2005), 32352720 (2020)). In addition, in vitro studies have reported that this variant has a deleterious effect on CFTR protein expression and channel activity (PMID: 12952861 (2003)), however, further research is needed. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJun 20, 2022Published functional studies demonstrate a damaging effect: reduced chloride channel activity and chloride/bicarbonate exchange activity (Lee 2003); Although this variant has not been reported in the homozygous or compound heterozygous state in individuals with cystic fibrosis, it has been reported in individuals of Asian ancestry with CFTR-related disorders (Gallati 2009, Steiner 2011, Cho 2016, Luo 2021); Some case control studies suggest this variant may be associated with pancreatitis in the Asian population (Fujiki 2004, Nakano 2015, Zou 2018, Iso 2019); 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: 27578509, 21520337, 16678503, 20981092, 20021716, 16187186, 30420730, 25492507, 17719933, 26089335, 28608624, 30450785, 28687971, 15121783, 31180159, 35119551, 12952861, 23514810, 33663443, 32777524, 30992994) -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 09, 2023PP3, PM3 -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesOct 11, 2019The CFTR c.4056G>C; p.Gln1352His variant (rs113857788) has been reported in multiple individuals diagnosed with CFTR-related disorders, such as congenital bilateral absence of vas deferens (Anzai 2003, Danziger 2004, Ratbi 2007, Steiner 2011, Li 2012) and pancreatitis (Lee 2003, Keiles 2006). In multiple affected individuals, this variant has been found in trans to other pathogenic CFTR variants (Anzai 2003, Steiner 2011, Li 2012). It has also been observed at a significantly higher frequency in Asian pancreatitis patients than unaffected individuals (Lee 2003, Fujiki 2004). Expression of the variant protein in a cell line reveals a significant reduction in mature CFTR protein detected compared to wildtype (Lee 2003). The variant is listed in ClinVar (Variation ID: 7237) and is observed in the general population database at a frequency of 0.1% (275/282620 alleles, including three homozygotes) in the Genome Aggregation Database. The glutamine at residue 1352 is highly conserved and computational algorithms (PolyPhen-2, SIFT) predict that the variant is deleterious. Based on available information, the variant is considered to be mildly pathogenic. References: Anzai C et al. CFTR gene mutations in Japanese individuals with congenital bilateral absence of the vas deferens. J Cyst Fibros. 2003 2(1):14-8. Danziger K et al. Improved detection of cystic fibrosis mutations in infertility patients with DNA sequence analysis. Hum Reprod. 2004 19(3):540-6. Fujiki K et al. Genetic evidence for CFTR dysfunction in Japanese: background for chronic pancreatitis. J Med Genet. 2004 41(5):e55. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 33(3):221-7. Lee J et al. A haplotype-based molecular analysis of CFTR mutations associated with respiratory and pancreatic diseases. Hum Mol Genet. 2003 12(18):2321-32. 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. 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. 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. -
CFTR-related disorders Pathogenic:2Benign:1
Likely pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenMay 12, 2021- -
Pathogenic, criteria provided, single submittercurationCFTR-FranceJan 29, 2018- -
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 27, 2017This 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. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 04, 2023Variant summary: CFTR c.4056G>C (p.Gln1352His) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains 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 0.00066 in 1619220 control chromosomes, predominantly at a frequency of 0.019 within the East Asian subpopulation in the gnomAD database, including 16 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis phenotype (0.013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant was found with even higher allele frequencies in several East Asian subpopulations, e.g. in the Japanese (with an allele frequency of 0.023 from about 14,000 healthy Japanese individuals in the jMorp database [PMID: 33179747]) and in the Vietnamese (with an allele frequency of 0.05 in 406 unrelated healthy Kinh Vietnamese individuals [PMID: 31180159]), suggesting this variant may be a benign polymorphism found primarily in East Asian populations. On the other hand, the c.4056G>C variant is frequently reported in men with CBAVD in conjunction with a second pathogenic variant, especially the 5T allele. However, one study reported the variant in two unaffected siblings who also carried a pathogenic CFTR mutation in trans (p.Y122X), including an apparently fertile male, suggesting the variant may not be fully penetrant or is not pathogenic (Bienvenu_2005). A recent study found the variant in 32/276 Chinese CAVD patients (i.e. with an allele frequency of 5.98%, including 1 homozygote), and in only 1 allele from 50 control individuals (Luo_2021). This variant is also seen with other phenotypes such as CF, pancreatitis, asthma, nontuberculous mycobacterial lung disease, and bronchiectasis, and the risk association score from several independent publications suggest that this variant is possibly associated with these CF-related phenotypes. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-30% of normal activity (Lee_2003). The following publications have been ascertained in the context of this evaluation (PMID: 15463840, 16596947, 17539902, 28603918, 9272157, 15121783, 20021716, 29997923, 17003641, 33663443, 31180159, 12952861, 22483971, 32777524, 25492507, 16678503, 20558957, 29520692, 17329263, 33374015, 31682332, 21520337, 28608624, 19812525, 20233062). Fifteen submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign/likely benign (n=3), pathogenic/likely pathogenic (n=3) and VUS (n=9). Based on the evidence outlined above, the variant was classified as VUS. -
CFTR-related condition Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 18, 2024The CFTR c.4056G>C variant is predicted to result in the amino acid substitution p.Gln1352His. This variant has been reported in patients with several different phenotypes including asthma, alcoholic chronic pancreatitis, idiopathic chronic pancreatitis, azoospermic males, and bronchiectasis (Cho et al. 2016. PubMed ID: 27578509; Gallati et al. 2009. PubMed ID: 20021716; Kondo et al. 2015. PubMed ID: 26089335; Pall et al. 2007. PubMed ID: 17719933). The c.4056G>C (p.Gln1352His) variant has been found at higher rates in Asian patients with pancreatitis (12.3%) compared to unaffected controls (3.7%) (Fujiki et al. 2004. PubMed ID: 15121783). However, the majority of these studies were conducted in Eastern Asian population cohorts where the c.4056G>C variant is found at a higher allele frequency. Functional studies in CHO cell lines indicate the p.Gln1352His change decreases CFTR protein expression and chloride channel function (Lee et al. 2003. PubMed ID: 12952861; Fujiki et al. 2004. PubMed ID: 15121783; Ngiam et al. 2006. PubMed ID: 16678503). However, no family studies have been conducted to determine if the c.4056G>C variant segregates with disease in individual families and to our knowledge, no homozygous c.4056G>C individuals have been reported with a CFTR-related disorder. This variant has been observed with a minor allele frequency of ~1.3% in East Asians, including 3 homozygous individuals (http://gnomad.broadinstitute.org/variant/7-117304834-G-C). The c.4056G>C has several conflicting interpretations in ClinVar ranging from benign to pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/7237). It is possible that the c.4056G>C variant exhibits incomplete penetrance or is a risk allele for disease. However, without additional conclusive evidence, the clinical significance of this variant remains uncertain. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Uncertain
0.14
D
BayesDel_noAF
Pathogenic
0.44
Cadd
Benign
22
Dann
Uncertain
1.0
DEOGEN2
Pathogenic
0.97
D;D;.
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.97
D;D;D
MetaRNN
Benign
0.015
T;T;T
MetaSVM
Uncertain
0.77
D
MutationAssessor
Pathogenic
3.4
M;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.74
T
PROVEAN
Uncertain
-4.2
D;D;.
REVEL
Pathogenic
0.92
Sift
Pathogenic
0.0
D;D;.
Sift4G
Pathogenic
0.0010
D;D;.
Polyphen
1.0
D;.;.
Vest4
0.99
MutPred
0.99
Gain of catalytic residue at M1354 (P = 0.0865);.;.;
MVP
1.0
MPC
0.018
ClinPred
0.16
T
GERP RS
3.6
Varity_R
0.94
gMVP
0.96

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.

Other links and lift over

dbSNP: rs113857788; hg19: chr7-117304834; COSMIC: COSV99134274; API