NM_000492.4:c.346G>A

Variant names:

• chr7-117530971-G-A
• rs397508571
• NM_000492.4:c.346G>A

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.346G>A​(p.Glu116Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002241405: Experimental studies have shown that this missense change affects CFTR function (PMID:11278813, 29805046, 30046002).; SCV002618795: "In vitro studies demonstrated that this alteration affects protein chloride channel current and transport to the cell membrane (Cui et al. J Gen Physiol. 2014;144(2):159-79; Hammerle et al. J. Biol. Chem. 2001 May; 276(18):14848-54; Lu et al. J. Biol. Chem. 1998 Jan; 273(1):568-76)."; SCV004020684: "At least one publication reports experimental evidence evaluating an impact on protein function demonstrating reduced transport of mature CFTR protein to cell surface and destabalization of the open state of chloride channel (Hammerle_2001)"; SCV000883591: Functional studies demonstrate destabilization of the open state of the chloride channel and slightly reduced transport of mature CFTR protein to the cell surface (Hammerle 2001).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E116Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:7 O:1
• Conservation: PhyloP100: 9.52
• Publications: 10 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: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002241405: Experimental studies have shown that this missense change affects CFTR function (PMID: 11278813, 29805046, 30046002).; SCV002618795: "In vitro studies demonstrated that this alteration affects protein chloride channel current and transport to the cell membrane (Cui et al. J Gen Physiol. 2014;144(2):159-79; Hammerle et al. J. Biol. Chem. 2001 May; 276(18):14848-54; Lu et al. J. Biol. Chem. 1998 Jan; 273(1):568-76)."; SCV004020684: "At least one publication reports experimental evidence evaluating an impact on protein function demonstrating reduced transport of mature CFTR protein to cell surface and destabalization of the open state of chloride channel (Hammerle_2001)"; SCV000883591: Functional studies demonstrate destabilization of the open state of the chloride channel and slightly reduced transport of mature CFTR protein to the cell surface (Hammerle 2001).
• PM1: In a hotspot region, there are 17 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 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 chr7-117530971-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2735077.
• 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, 0.973
• PP5: Variant 7-117530971-G-A is Pathogenic according to our data. Variant chr7-117530971-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 53754.Status of the report is reviewed_by_expert_panel, 3 stars.

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.346G>A	p.Glu116Lys	missense	Exon 4 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.346G>A	p.Glu116Lys	missense	Exon 4 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.346G>A	p.Glu116Lys	missense	Exon 4 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.346G>A	p.Glu116Lys	missense	Exon 4 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
4	-	-	Cystic fibrosis (5)
1	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C5924204:CFTR-related disorder (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.7	L
PhyloP100		9.5
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.88		Gain of methylation at E116 (P = 0.0016)
MVP		1.0
MPC		0.0084
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.84
gMVP		0.95
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397508571; hg19: chr7-117171025; COSMIC: COSV50048108;