rs201386642

chr7-117594945-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000492.4(CFTR):c.2506G>T(p.Asp836Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000406 in 1,612,886 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D836D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:11 B:2
• Conservation: PhyloP100: 9.06

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19826666).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2506G>T	p.Asp836Tyr	missense_variant	15/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2506G>T	p.Asp836Tyr	missense_variant	15/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000382 AC: 58 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000442 AC: 111 AN: 251312 Hom.: 0 AF XY: 0.000464 AC XY: 63 AN XY: 135828

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000409 AC: 597 AN: 1460760 Hom.: 2 Cov.: 30 AF XY: 0.000378 AC XY: 275 AN XY: 726772

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.00174

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.000464

GnomAD4 genome AF: 0.000381 AC: 58 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30 AN XY: 74364

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000356 Hom.: 0

Bravo AF: 0.000314

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000412 AC: 50

EpiCase AF: 0.0000545

EpiControl AF: 0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:5 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3_STR, PP3, BS3, BP2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 18, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 09, 2023	The p.D836Y variant (also known as c.2506G>T), located in coding exon 15 of the CFTR gene, results from a G to T substitution at nucleotide position 2506. The aspartic acid at codon 836 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was reported in trans with the p.F508del mutation in a newborn with a negative newborn screen and sweat test (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46). In addition, this alteration was identified in an individual who had p.F508del and normal sweat test (de Gracia J et al. Thorax, 2005 Jul;60:558-63), as well as two affected newborns that had two known pathogenic mutations in CFTR (Salinas DB et al. PLoS ONE, 2016 May;11:e0155624); however, the phase is not known. This alteration was also described in study cohorts of cystic fibrosis; however, clinical details were limited (des Georges M et al. J. Cyst. Fibros., 2004 Dec;3:265-72; Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In CFBE cells, this variant demonstrated 122% of wild type CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Pathogenic:1 Uncertain:4

Likely pathogenic, flagged submission	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 13, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 27, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 16, 2020	The CFTR c.2506G>T; p.Asp836Tyr variant (rs201386642) has been reported in patients with diagnoses or symptoms of CF (des Georges 2004, de Gracia 2005, Schrijver 2005, CFTR2 database). However, p.Asp836Tyr has also been reported in two individuals with pancreatic-insufficient CF (Salinas 2016) who were compound heterozygotes for two known severe pathogenic variants (F508del and 2215insG). The p.Asp836Tyr variant is listed in ClinVar (Variation ID: 53505) and is found in the Latino population with an overall frequency of 0.18% (62/35414 alleles) in the Genome Aggregation Database. The aspartate at codon 836 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant has an impact on the protein. However, the p.Asp836Tyr variant exhibits wildtype chloride channel activity in conductance assays (Raraigh 2018). Due to conflicting information, the clinical significance of the p.Asp836Tyr variant is uncertain at this time. References: CFTR2 database: https://www.cftr2.org/ de Gracia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005 Jul;60(7):558-63. des Georges M et al. High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. J Cyst Fibros. 2004 Dec;3(4):265-72. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Salinas D et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016 May 23;11(5):e0155624. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005 May;7(2):289-99. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 06, 2018	The p.Asp836Tyr variant in CFTR has been reported in 2 individuals with cystic f ibrosis; however it was unclear if a second CFTR variant was found in these indi viduals (des Georges 2004, Schrijver 2005). It was also identified in the compou nd heterozygous state in 4 individuals who had at least one additional pathogeni c variant in CFTR (de Gracia 2005, Narzi 2007, Salinas 2016). In two of these in dividuals, two other pathogenic variants in CFTR were also identified, suggestin g that the p.Asp836Tyr variant may not be the primary cause of disease (Salinas 2016). This variant has also been reported by other clinical laboratories in Cli nVar (Variation ID# 53505) and has been identified in 0.17% (60/34400) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org; dbSNP rs201386642). Although this variant has been seen in the genera l population, its frequency is not high enough to rule out a pathogenic role. Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. In summary, due to conflicting evi dence, the clinical significance of the p.Asp836Tyr variant is uncertain. ACMG/A MP Criteria applied: PM3_Strong, BP2. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 23, 2020	Variant summary: CFTR c.2506G>T (p.Asp836Tyr) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00044 in 277324 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00044 vs 0.013), allowing no conclusion about variant significance. The variant, c.2506G>T, has been reported in the literature in compound heterozygosity with deltaF508 in patients with an equivocal diagnosis of CF as evidenced by negative sweat chloride levels and pancreatic sufficiency (example, Narzi_2007, deGracia_2005) as well as in patients with pancreatically insufficient classic CF phenotype who had two other pathogenic CFTR variants that could explain the diagnosis (Salinas_2016). These data provide supportive evidence for a benign role. Furthermore, in a recent study evaluating CFTR function by short circuit current measurement in a cell system, the variant of interest was found to have 121% of WT-CFTR function (Raraigh _2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, at-least one of whom has set a final classification as benign while another laboratory has re-classified the variant from likely pathogenic to uncertain significance citing overlapping evidence utilized in the context of this evaluation (Benign, n=1; VUS, n=5). Furthermore, the CFTR2 database reports this variant as not causative of CF. Based on the absence of concrete evidence supporting a disease causing outcome in literature spanning over 15 years as evidence outlined above, the variant is re-classified as benign. -

Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Oct 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;.;D;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N;.;N;.
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;.;D;.
Sift4G	Pathogenic	0.0	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.90
MVP		0.99
MPC		0.0096
ClinPred		0.078	T
GERP RS		5.3
Varity_R		0.56
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs201386642; hg19: chr7-117234999;