rs397508375

chr7-117592584-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000492.4(CFTR):c.2417A>G(p.Asp806Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,377,414 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. D806E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:5 O:1
• Conservation: PhyloP100: 6.69

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945
• PP5: Variant 7-117592584-A-G is Pathogenic according to our data. Variant chr7-117592584-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53487.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=5, not_provided=1, Likely_pathogenic=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2417A>G	p.Asp806Gly	missense_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2417A>G	p.Asp806Gly	missense_variant	14/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000111 AC: 2 AN: 179966 Hom.: 0 AF XY: 0.0000105 AC XY: 1 AN XY: 94970

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000495

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000113

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 18 AN: 1377414 Hom.: 0 Cov.: 31 AF XY: 0.0000177 AC XY: 12 AN XY: 678654

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000349

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000290

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000928

Gnomad4 OTH exome AF: 0.0000703

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:2 Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 13, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 806 of the CFTR protein (p.Asp806Gly). This variant is present in population databases (rs397508375, gnomAD 0.005%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 12544470, 30548586, 32429104). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53487). 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 with a positive predictive value of 80%. 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	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 18, 2023	The p.D806G variant (also known as c.2417A>G), located in coding exon 14 of the CFTR gene, results from an A to G substitution at nucleotide position 2417. The aspartic acid at codon 806 is replaced by glycine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with cystic fibrosis that also carried p.F508del (Strom CM et al. Genet Med;5:9-14; Petrova NV et al. Clin Genet, 2019 03;95:444-447). This alteration was also reported in trans with the p.F508del mutation in a newborn with a negative sweat test (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46). This alteration has also been identified in an individual diagnosed with pancreatic cancer (Tavano F et al. Mol Med, 2023 Jan;29:14). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Pathogenic:1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2023	Observed with other CFTR variants, phase (cis or trans) unknown, in individuals with sweat chloride levels or nasal potential difference (NPD) within normal range (Narzi 2007, Tridello 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34426522, 30938940, 30548586, 17594398, 12544470, 32429104, 33572515, 25880441, 19897426, 25735457, 27423539, 34996830, 34405919, 36717774) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 23, 2019	The CFTR c.2417A>G; p.Asp806Gly variant (rs397508375) is reported in the literature in the compound heterozygous state with a second pathogenic variant in individuals affected with cystic fibrosis (Narzi 2007, Strom 2003). This variant is reported in ClinVar (Variation ID: 53487), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The aspartic acid at codon 806 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, given the lack of clinical and functional data, the significance of the p.Asp806Gly variant is uncertain at this time. References: Narzi L et al. Does cystic fibrosis neonatal screening detect atypical CF forms? Extended genetic characterization and 4-year clinical follow-up. Clin Genet. 2007 Jul;72(1):39-46. Strom CM et al. Extensive sequencing of the cystic fibrosis transmembrane regulator gene: assay validation and unexpected benefits of developing a comprehensive test. Genet Med. 2003 Jan-Feb;5(1):9-14. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 02, 2023	- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

CFTR-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 16, 2020

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 25, 2023

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Dec 18, 2023

Variant summary: CFTR c.2417A>G (p.Asp806Gly) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) 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 1.1e-05 in 179966 control chromosomes(gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2417A>G has been reported in (assumed) compound heterozygous individuals affected with (suspected) cystic fibrosis (e.g. Strom_2003, Picci_2010), however, it was also observed in trans with a pathogenic variant (p.F508del) in a newborn with a negative sweat test (Narzi_2007). In addition, the variant was listed to be found in cohorts of CF patients and newborns with positive screening tests, however no second variant was specified in these cases (e.g. Atag_2019, Petrova_2020, Bozdogan_2021). These data do not allow clear conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30938940, 33572515, 25880441, 34405919, 17594398, 30548586, 19897426, 25735457, 34996830, 12544470, 36717774). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant sa VUS (n=5) and likely pathogenic (n=3). 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	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.51
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;D;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.4	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.4	D;.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.;D;.
Sift4G	Uncertain	0.0030	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.63
MutPred		0.78		Gain of sheet (P = 0.0827);.;.;.;
MVP		1.0
MPC		0.0049
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.70
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs397508375; hg19: chr7-117232638;