7-117534344-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 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).

• 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:2 U:3
• Conservation: PhyloP100: 0.880

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• 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 ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558712.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.558C>G	p.Asn186Lys	missense_variant	5/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.558C>G	p.Asn186Lys	missense_variant	5/27	1	NM_000492.4	P2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2023	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). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive CFTR-related conditions (PMID: 16454991, 25580864, 30811104). ClinVar contains an entry for this variant (Variation ID: 558712). 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. Experimental studies have shown that this missense change affects CFTR function (PMID: 31893350). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 06, 2018	- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 29, 2023

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 21, 2022

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 an individual affected with Cystic Fibrosis, who carried a 2nd pathogenic variant (Liu_2015), 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). Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant as VUS (n=2) or Likely Pathogenic (n=1). 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
MutationTaster	Benign	1.0	D;D
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

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

Other links and lift over

dbSNP: rs397508753; hg19: chr7-117174398;