rs397508316

Positions:

• chr7-117592049-G-A
• chr7-117592049-G-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.1882G>A​(p.Gly628Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,453,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:5 O:1
• Conservation: PhyloP100: 9.23

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 Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_000492.4 (CFTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 7-117592049-G-A is Pathogenic according to our data. Variant chr7-117592049-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 53408.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1882G>A	p.Gly628Arg	missense_variant	14/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1882G>A	p.Gly628Arg	missense_variant	14/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000409 AC: 1 AN: 244320 Hom.: 0 AF XY: 0.00000758 AC XY: 1 AN XY: 131882

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000352

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1453078 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 2 AN XY: 722014

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000238

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5 Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Apr 23, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2022	Variant summary: CFTR c.1882G>A (p.Gly628Arg) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) 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 4.1e-06 in 244320 control chromosomes. c.1882G>A has been reported in the literature as a compound heterozygous genotype with p.F508del in at-least 4 individuals, to include three with Cystic Fibrosis and one with CBAVD (example, Claustres_2000, De Boeck_2005), as a non-informative genotype (second allele/zygosity not specified) in individuals with Cystic Fibrosis (Fanen_1992, Jorissen_1999), and as a homozygous or compound heterozygous complex allele in cis with p.Ser1235Arg (c.[1882G>A;3705T>G]) (p.[Gly628Arg;Ser1235Arg]) in individuals with Cystic Fibrosis (example, Mercier_1995, Sanchez_2016). The compound heterozygote with the complex allele carried c.946delT on the other allele (Sanchez_2016). At-least one study provides evidences against the pathogenicity of the p.Ser1235Arg variant suggesting that p.Gly628Arg (this variant) might be causative in settings of CF or CBAVD (example, Rene_2011). These data indicate that the variant in isolation is likely to be associated with disease, although the possibility of incomplete genotyping in the four reported compound heterozygotes in isolation with this variant and p.F508del captured above cannot be entirely ruled out. At least two publications report experimental evidence evaluating an impact on protein function (example, Wei_2000, Billet_2010). The most pronounced variant effect results in defective maturation of the CFTR protein (Billet_2010 and Wei_2000). This is consistent with the finding(s) of reduced/defective CFTR channel activity measured as whole cell currents in both these studies. However, in one of these reports, the authors suggest caution with the interpretation of these electrophysiological data due to a lack of confirmation of these observations at the level of single channel measurements. Whole cell currents do not always correlate with single channel activities of CFTR proteins, and are dependent on the number of chloride channels present in the cell membrane. In particular, the double mutant Gly628Arg/Ser1235Arg induced a significantly lower cAMP dependent chloride transport activity (0.11 uA) than Gly628Arg (0.19 uA) or Ser1235Arg (0.39 uA) CFTR alone (Wei_2000). Two clinical diagnostic laboratories, an expert panel (CFTR2) and a database (CFTR-France) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Mar 26, 2020	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 11, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;.;T;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.7	D;.;D;.
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0010	D;.;D;.
Sift4G	Uncertain	0.0030	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.99
MutPred		0.95		Gain of phosphorylation at S631 (P = 0.1011);.;.;.;
MVP		1.0
MPC		0.016
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.97

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: rs397508316; hg19: chr7-117232103;