NM_000492.4:c.166G>A

Variant names:

• chr7-117509035-G-A
• rs397508256
• NM_000492.4:c.166G>A

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM1 PP2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.166G>A​(p.Glu56Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000118 in 1,442,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic,drug response (★★★). ClinVar reports functional evidence for this variant: "SCV001582754: Experimental studies have shown that this missense change affects CFTR function (PMID:23891399, 23924900).; SCV002704422: Functional studies also determined that the effect of this variant on the CFTR protein was deleterious. Five individuals with cystic fibrosis were reported with this variant, but the second pathogenic mutation and clinical information on these patients was not available (The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 25, 2014 and Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167).; SCV004226564: PS3". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E56D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.9916
• Clinical Significance: Pathogenic; drug response reviewed by expert panel P:9 O:1
• Conservation: PhyloP100: 5.92
• Publications: 36 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 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001582754: Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23924900).; SCV002704422: Functional studies also determined that the effect of this variant on the CFTR protein was deleterious. Five individuals with cystic fibrosis were reported with this variant, but the second pathogenic mutation and clinical information on these patients was not available (The Clinical and Functional Translation of CFTR (CFTR2); available at http://cftr2.org. Accessed March 25, 2014 and Sosnay PR et al. Nat Genet. 2013;45(10):1160-1167).; SCV004226564: PS3
• PM1: In a hotspot region, there are 8 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: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 7-117509035-G-A is Pathogenic according to our data. Variant chr7-117509035-G-A is described in ClinVar as Pathogenic|drug_response. ClinVar VariationId is 53325.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.166G>A	p.Glu56Lys	missense splice_region	Exon 3 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.166G>A	p.Glu56Lys	missense splice_region	Exon 3 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.166G>A	p.Glu56Lys	missense splice_region	Exon 3 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.166G>A	p.Glu56Lys	missense splice_region	Exon 3 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250694 AF XY: 0.00000738

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: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000118 AC: 17 AN: 1442320 Hom.: 0 Cov.: 28 AF XY: 0.0000139 AC XY: 10 AN XY: 719018

African (AFR) AF: 0.00 AC: 0 AN: 33090

American (AMR) AF: 0.00 AC: 0 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39582

South Asian (SAS) AF: 0.00 AC: 0 AN: 85876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52900

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000155 AC: 17 AN: 1094728

Other (OTH) AF: 0.00 AC: 0 AN: 59702

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000232 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic; drug response

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.9	M
PhyloP100		5.9
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.69
Sift	Benign	0.072	T
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.93
MutPred		0.83		Gain of MoRF binding (P = 0.0113)
MVP		0.99
MPC		0.0039
ClinPred		0.83	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.91
Mutation Taster		=21/79	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.89
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: rs397508256; hg19: chr7-117149089; COSMIC: COSV99135139; COSMIC: COSV99135139;