rs121908751

chr7-117530899-G-Achr7-117530899-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):c.274G>A(p.Glu92Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E92D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.9962
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 9.52

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 13 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 14 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117530899-G-A is Pathogenic according to our data. Variant chr7-117530899-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7181.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117530899-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.274G>A	p.Glu92Lys	missense_variant, splice_region_variant	4/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.274G>A	p.Glu92Lys	missense_variant, splice_region_variant	4/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1447030 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 720964

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 26, 2022	The p.E92K pathogenic mutation (also known as c.274G>A and 406G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 274. This change occurs in the first base pair of coding exon 4. The glutamic acid at codon 92 is replaced by lysine, an amino acid with some similar properties. This mutation was identified in the homozygous state in a child with cystic fibrosis, elevated sweat chloride level, pancreatic sufficiency and history of Pseudomonas infection (Stanke F et al. J Med Genet. 2008;45(1):47-54). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 07/26/2022). This variant has <25% of wild type quantity and <10% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 07/26/2022; Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). In addition, in vitro functional studies in FRT cells with this variant showed little to no mature CFTR protein (Van Goor F et al. J Cyst Fibros. 2014;13(1):29-36) . Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1993	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CFTR function (PMID: 18306312, 23891399, 23924900, 28448979). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 7181). This missense change has been observed in individual(s) with cystic fibrosis, pancreatic insufficiency and congenital bilateral absence of the vas deferens (CBAVD) (PMID: 10875853, 18178635, 29504914). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 92 of the CFTR protein (p.Glu92Lys). -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Sep 14, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2017	Variant summary: The CFTR c.274G>A (p.Glu92Lys) variant involves the alteration of a conserved nucleotide located in the ABC transporter type 1, transmembrane domain (InterPro). The variant affects the first nucleotide in exon 4. 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 117032 control chromosomes. The variant has been reported in numerous CF alleles in the literature, and functional in vitro analysis has shown the variant to result in defective CFTR processing and <10% chloride transport (Sosnay_2013, Van Goor_2014) compared to WT. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Sep 04, 2017	- -

Cystic fibrosis;na:CFTR-related disorders Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

CFTR-related disorders Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 04, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D;D;.;.;D;.
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;.;.;D;.
Sift4G	Pathogenic	0.0	D;D;.;.;D;.
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.94
MutPred		0.95		.;Gain of MoRF binding (P = 0.0121);Gain of MoRF binding (P = 0.0121);Gain of MoRF binding (P = 0.0121);Gain of MoRF binding (P = 0.0121);Gain of MoRF binding (P = 0.0121);
MVP		1.0
MPC		0.014
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.88
SpliceAI score (max)		0.17		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: rs121908751; hg19: chr7-117170953; COSMIC: COSV50055904;