rs121908759

Variant names:

• chr7-117592032-G-A
• rs121908759
• NM_000492.4:c.1865G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS3 PM1 PP2 PP3 PP5

The NM_000492.4(CFTR):​c.1865G>A​(p.Gly622Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00012 in 1,603,502 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV000711290: "In vitro functional studies provide some evidence that the p.Gly622Asp variant may impact protein function (Norez 2008, Billet 2010)"" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G622G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000094 (2 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:23 U:1
• Conservation: PhyloP100: 9.23
• Publications: 33 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: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• 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: Likely_pathogenic. The variant received 9 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000711290: "In vitro functional studies provide some evidence that the p.Gly622Asp variant may impact protein function (Norez 2008, Billet 2010)"; SCV000915206: Functional studies in COS1, COS7 and HEK 293 cells demonstrated that the p.Gly622Asp variant resulted in abnormal intracellular trafficking and reduced CFTR activity (Vankeerberghen et al. 1998; Norez et al. 2008; Billet et al. 2010).; SCV001174031: Functional studies have demonstrated that this alteration results in lower intrinsic chloride channel activities, altered protein trafficking, reduced levels of fully mature CFTR protein, and reduced chloride conductance compared to wild type (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9; Norez C et al. J. Pharmacol. Exp. Ther., 2008 Apr;325:89-99; Billet A et al. J. Biol. Chem., 2010 Jul;285:22132-40; Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077; Han ST et al. JCI Insight, 2018 Jul;3:).; SCV001719369: Experimental studies have shown that this missense change affects CFTR function (PMID: 9736778, 18230692, 20435887, 20932301).; SCV002047967: Functional characterization of the variant protein indicates a defect in CFTR processing and maturation, leading to a reduced chloride transport activity (Billet 2010, Raraigh 2018, Vankeerberghen 1998). PMID: 20435887. PMID: 29805046. PMID: 9736778.; SCV002503746: "Moderately reduced protein function has been shown with stable expression of the variant in a human airway cell line, and significantly lower intrinsic chloride channel activities in in vitro assays in COS1 cells." PMID:9736778, PMID:29805046; SCV000601063: Several functional studies have reported that this variant affects proper CFTR function (PMID 20435887 (2010), 18230692 (2008), 9736778 (1998), 30046002 (2018)).; SCV001982355: Published functional studies are conflicting: normal or reduced protein maturation, reduced chloride transport activity, and reduced protein function (PMID: 20435887, 18230692, 29805046, 9736778);; SCV004719395: Experimental studies indicate this variant impacts protein function (Norez et al. 2008. PubMed ID: 18230692).
• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000492.4
• 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, 0.764
• PP5: Variant 7-117592032-G-A is Pathogenic according to our data. Variant chr7-117592032-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35833.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1865G>A	p.Gly622Asp	missense	Exon 14 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1865G>A	p.Gly622Asp	missense	Exon 14 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1865G>A	p.Gly622Asp	missense	Exon 14 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1778G>A	p.Gly593Asp	missense	Exon 13 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000103 AC: 25 AN: 242874 AF XY: 0.0000762

Gnomad AFR exome AF: 0.000752

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000611

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000341

GnomAD4 exome AF: 0.0000937 AC: 136 AN: 1451302 Hom.: 2 Cov.: 31 AF XY: 0.0000832 AC XY: 60 AN XY: 721128

African (AFR) AF: 0.000458 AC: 15 AN: 32754

American (AMR) AF: 0.00 AC: 0 AN: 42548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25686

East Asian (EAS) AF: 0.000530 AC: 21 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 83576

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53224

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108326

Other (OTH) AF: 0.00165 AC: 99 AN: 59878

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74408

African (AFR) AF: 0.00118 AC: 49 AN: 41532

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000434 Hom.: 1

Bravo AF: 0.000461

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
8	1	-	Cystic fibrosis (9)
6	-	-	not provided (6)
2	-	-	CFTR-related disorder (2)
2	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)
1	-	-	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.97
MVP		1.0
MPC		0.015
ClinPred		0.57	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.96
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: rs121908759; hg19: chr7-117232086;