rs80055610

Positions:

• chr7-117587833-G-A
• chr7-117587833-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.1679G>A​(p.Arg560Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000998 in 1,402,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 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. R560S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:8
• Conservation: PhyloP100: 8.82

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 18 ACMG points.

• PM1: In a helix (size 13) in uniprot entity CFTR_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) 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 chr7-117590353-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 7-117587833-G-A is Pathogenic according to our data. Variant chr7-117587833-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7156.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117587833-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1679G>A	p.Arg560Lys	missense_variant, splice_region_variant	12/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1679G>A	p.Arg560Lys	missense_variant, splice_region_variant	12/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000998 AC: 14 AN: 1402616 Hom.: 0 Cov.: 23 AF XY: 0.00000713 AC XY: 5 AN XY: 701596

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: 0.0000132

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 16, 2022	The p.R560K variant (also known as c.1679G>A), located in coding exon 12 of the CFTR gene, results from a G to A substitution at nucleotide position 1679. The arginine at codon 560 is replaced by lysine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. 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 06/16/2022). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. This amino acid position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In addition, as a missense substitution this is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
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.1679G>A (p.Arg560Lys) variant involves the alteration of a conserved nucleotide at the end of exon 12 and is located in P-loop containing nucleoside triphosphate hydrolase, AAA+ ATPase and/or ABC transporter 1 domain of the protein (InterPro). 4/5 in silico tools predict damaging outcome for this variant. In addition, 5/5 splice prediction tools predict that this variant weakens the canonical 5' splice donor site. This variant has been reported in several CF patients, majority of patients characterized to be pancreatic insufficient (Ferec_1992, Osika_1999, Scotet_2003, Sosnay_2013) and is absent in 118816 control chromosomes from ExAC. Functional analysis shows that this variant leads to defective chloride channel and/or CFTR processing (Sosnay_2013). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Other missense changes at the same residue, namely p.Arg560Gly, p.Arg560Ser, and p.Arg560Thr have been reported to associate with CF, indicating Arg560 is a mutational hot-spot. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 560 of the CFTR protein (p.Arg560Lys). This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with cystic fibrosis (PMID: 23974870). ClinVar contains an entry for this variant (Variation ID: 7156). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg560 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15371902, 23974870). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1992	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Apr 16, 2018	- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.8	D;.;D;.
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;.;D;.
Sift4G	Uncertain	0.012	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.94
MutPred		0.99		Loss of methylation at R560 (P = 0.0407);.;.;.;
MVP		1.0
MPC		0.017
ClinPred		1.0	D
GERP RS		5.3
Varity_R		1.0
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.82		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.82		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80055610; hg19: chr7-117227887;