NM_000492.4:c.567C>A

Variant names:

• chr7-117534353-C-A
• rs397508755
• NM_000492.4:c.567C>A

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.567C>A​(p.Asn189Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N189N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 O:1
• Conservation: PhyloP100: 2.31
• Publications: 6 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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 26 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, 0.955
• PP5: Variant 7-117534353-C-A is Pathogenic according to our data. Variant chr7-117534353-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 54002.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.567C>A	p.Asn189Lys	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.567C>A	p.Asn189Lys	missense_variant	Exon 5 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1404054 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 702216

African (AFR) AF: 0.00 AC: 0 AN: 32248

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.00 AC: 0 AN: 39358

South Asian (SAS) AF: 0.00 AC: 0 AN: 85026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1060038

Other (OTH) AF: 0.00 AC: 0 AN: 58520

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:1 Other:1

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, PM2_SUP, PP3 -

Nov 19, 2019

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.N189K variant (also known as c.567C>A), located in coding exon 5 of the CFTR gene, results from a C to A substitution at nucleotide position 567. The asparagine at codon 189 is replaced by lysine, an amino acid with similar properties. This variant was confirmed in trans with a frameshift variant in a Chinese individual with cystic fibrosis (CF) with pulmonary manifestations and elevated sweat chloride levels (Li N et al. Chin. Med. J., 2006 Jan;119:103-9). In a cohort of Chinese individuals with CF, this variant was detected in 4 of 22 individuals (Zheng B et al. Pediatr. Pulmonol., 2017 03;52:E11-E14). This variant was not reported in the gnomAD database, with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

not specified Uncertain:1

Jul 03, 2024

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.567C>A (p.Asn189Lys) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.567C>A has been reported in the literature as a biallelic compound heterozygous genotype in at-least one Chinese individual affected with Cystic Fibrosis and continues to be cited by others (example, Li_2006 cited in Zheng_2017, Shen_2022, Zacarias_2023). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 54002). 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	0.84
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.7	M;.;.;M
PhyloP100		2.3
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.1	N;.;.;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.015	D;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;.
Polyphen		1.0	D;.;.;.
Vest4		0.95
MutPred		0.90		Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);Loss of stability (P = 0.0205);
MVP		0.97
MPC		0.0076
ClinPred		0.94	D
GERP RS		3.7
Varity_R		0.76
gMVP		0.89
Mutation Taster		=14/86	disease causing (ClinVar)

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: rs397508755; hg19: chr7-117174407; COSMIC: COSV104985235; COSMIC: COSV104985235;