7-117664780-G-C

Position:

chr7-117664780-G-C

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).

Frequency

Genomes: 𝑓 0.00060 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 15 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

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]

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 transporter 2 (size 233) in uniprot entity CFTR_HUMAN there are 28 pathogenic changes around while only 3 benign (90%) 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 GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.4056G>C	p.Gln1352His	missense_variant	25/27	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.4056G>C	p.Gln1352His	missense_variant	25/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152198

Hom.:

Cov.:

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.:

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.:

Cov.:

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:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

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.:

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 provided	literature only	OMIM	Sep 15, 2003	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	May 12, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2023	The 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided

Pathogenic:1Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 09, 2023	PP3, PM3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 04, 2023	The 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 submitter	clinical testing	GeneDx	Jun 20, 2022	Published 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) -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 11, 2019	The 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 disorder

Pathogenic:2Uncertain:1Benign:1

Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	May 12, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 29, 2024	The 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. 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. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 20, 2024

Variant 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 0.00059 in 1614026 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). 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) and approximately 36% of normal chloride channel conductance relative to wildtype (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 9272157, 15121783, 12952861, 17539902, 16678503, 20233062, 19812525, 17329263, 17003641, 16596947, 15463840, 20021716, 21520337, 22483971, 25492507, 20558957, 28608624, 28603918, 29997923, 29520692, 31682332, 33374015, 32777524, 33663443, 31180159, 38388235). ClinVar contains an entry for this variant (Variation ID: 7237). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;D

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.4

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.74

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

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.

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