7-117534344-C-G

Variant names:

• chr7-117534344-C-G
• rs397508753
• NM_000492.4:c.558C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.558C>G​(p.Asn186Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,280 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:3
• Conservation: PhyloP100: 0.880
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 7-117534344-C-G is Pathogenic according to our data. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712. Variant chr7-117534344-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 558712.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.558C>G	p.Asn186Lys	missense_variant	Exon 5 of 27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.558C>G	p.Asn186Lys	missense_variant	Exon 5 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430280 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 713664

African (AFR) AF: 0.00 AC: 0 AN: 32784

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25908

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 85606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1083862

Other (OTH) AF: 0.00 AC: 0 AN: 59364

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:2

Jun 06, 2018

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Aug 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 31893350). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. ClinVar contains an entry for this variant (Variation ID: 558712). This missense change has been observed in individual(s) with autosomal recessive CFTR-related conditions (PMID: 16454991, 25580864, 30811104). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 186 of the CFTR protein (p.Asn186Lys). -

Sep 05, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 27, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Uncertain:1

Mar 31, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.558C>G (p.Asn186Lys) results in a non-conservative amino acid change located in the first 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 was absent in 250516 control chromosomes (gnomAD). The variant, c.558C>G, has been reported in the literature in two individuals affected with Cystic Fibrosis, who carried a 2nd pathogenic variant (Liu_2015, Shen_2022), and in multiple individuals affected with uni- or bilateral absence of the vas deferens, described as heterozygous, or co-occurring with VUS variants (Yuan_2019, Wang_2020, Luo_2021). These data do not allow clear conclusions about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated that the N186K variant protein had similar conductance to the WT channel (Linsdell_2020). In addition, a different variant, resulting in the same missense change, c.558C>A (p.Asn186Lys) has been evaluated VUS in ClinVar. The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 31893350, 25580864, 32777524, 35858753, 32020786, 30811104). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.7	M;.;.;M
PhyloP100		0.88
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.51	N;.;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.095	T;.;.;.
Sift4G	Uncertain	0.046	D;.;.;.
Polyphen		0.95	P;.;.;.
Vest4		0.88
MutPred		0.86		Gain of ubiquitination at N186 (P = 0.0185);Gain of ubiquitination at N186 (P = 0.0185);Gain of ubiquitination at N186 (P = 0.0185);Gain of ubiquitination at N186 (P = 0.0185);
MVP		0.97
MPC		0.015
ClinPred		0.92	D
GERP RS		4.6
Varity_R		0.69
gMVP		0.90
Mutation Taster		=5/95	disease causing

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

Other links and lift over

dbSNP: rs397508753; hg19: chr7-117174398;