chr7-117592049-G-A

Variant names:

• chr7-117592049-G-A
• rs397508316
• NM_000492.4:c.1882G>A

Variant summary

Our verdict is Pathogenic. The variant received 27 ACMG points: 27P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP2 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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G628A) has been classified as Likely pathogenic.

• 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
• Publications: 16 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 27 ACMG points.

• PS1: Transcript NM_000492.4 (CFTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117592050-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 555466.
• 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, 0.991
• PP5: Variant 7-117592049-G-A is Pathogenic according to our data. Variant chr7-117592049-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 53408.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1882G>A	p.Gly628Arg	missense_variant	Exon 14 of 27	ENST00000003084.11	NP_000483.3

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000409 AC: 1 AN: 244320 AF XY: 0.00000758

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 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

African (AFR) AF: 0.00 AC: 0 AN: 32898

American (AMR) AF: 0.00 AC: 0 AN: 43080

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25750

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000238 AC: 2 AN: 84080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108678

Other (OTH) AF: 0.00 AC: 0 AN: 59970

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

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

Oct 24, 2022

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 23, 2015

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 26, 2020

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

-

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 11, 2019

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

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;.;.;.
PhyloP100		9.2
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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397508316; hg19: chr7-117232103;