Variant 7-117590404-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7

The NM_000492.4(CFTR):c.1731C>T(p.Tyr577Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,603,002 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

CFTR
NM_000492.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:1

Conservation

PhyloP100: -0.0580

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP7

Synonymous conserved (PhyloP=-0.058 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1731C>T	p.Tyr577Tyr	synonymous_variant	13/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1731C>T	p.Tyr577Tyr	synonymous_variant	13/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000856

AC:

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000208

AC:

AN:

250308

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135448

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000371

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000242

AC:

351

AN:

1450958

Hom.:

Cov.:

AF XY:

0.000238

AC XY:

172

AN XY:

721710

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.000315

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000951

Gnomad4 NFE exome

AF:

0.000289

Gnomad4 OTH exome

AF:

0.000201

GnomAD4 genome

AF:

0.0000855

AC:

AN:

152044

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000945

Gnomad4 NFE

AF:

0.000133

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000269

Hom.:

Bravo

AF:

0.000121

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 03, 2020	The CFTR c.1731C>T; p.Tyr577Tyr variant (rs55928397), is reported in the literature in an individual affected with cystic fibrosis (SickKids CFTR database). This variant is found in the non-Finnish European population with an overall allele frequency of 0.04% (46/128572 alleles) in the Genome Aggregation Database, and it is reported in ClinVar (Variation ID: 35832). This is a synonymous variant in a weakly conserved nucleotide; however, it occurs in an exonic splicing enhancer element and minigene assays indicate it may lead to increased skipping of exon 12 (Amaral 2004, Fernandez Alanis 2012, Pagani 2005), although this has not been demonstrated in patient cells with this variant. Given the lack of clinical and functional data, the significance of the c.1731C>T variant is uncertain at this time. References: SickKids CFTR database entry for p.Tyr577Tyr: http://www.genet.sickkids.on.ca/cftr/MutationDetailPage.external?sp=755 Amaral MD et al. Quantitative methods for the analysis of CFTR transcripts/splicing variants. J Cyst Fibros. 2004 Aug;3 Suppl 2:17-23. Fernandez Alanis et al. An exon-specific U1 small nuclear RNA (snRNA) strategy to correct splicing defects. Hum Mol Genet. 2012 Jun 1;21(11):2389-98. Pagani F et al. Synonymous mutations in CFTR exon 12 affect splicing and are not neutral in evolution. Proc Natl Acad Sci U S A. 2005 May 3;102(18):6368-72. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 11, 2022	The frequency of this variant in the general population, 0.00036 (46/128572 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with idiopathic chronic pancreatitis (PMIDs: 18687795 (2008) and 25492507 (2015)). Functional studies predict exon 12 skipping and did not show any detectable protein (PMIDs: 15463919 (2004), 22362925 (2012), 22591852 (2012), and 32935393 (2020)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CFTR mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 02, 2024	PM2_supporting, PS3 -

Cystic fibrosis

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2024	The c.1731C>T variant (also known as p.Y577Y), located in coding exon 13 of the CFTR gene, results from a C to T substitution at nucleotide position 1731. This nucleotide substitution does not change the amino acid at codon 577. Functional splicing assays have observed this variant to cause exon 12 skipping (exon 13 based on current exon numbering) using in vitro hybrid minigene transcripts, and authors suggested it may affect exonic splicing regulatory elements (Pagani F et al. Proc Natl Acad Sci U S A, 2005 May;102:6368-72; Fernandez Alanis E et al. Hum. Mol. Genet., 2012 Jun;21:2389-98; Donegà S et al. Hum Mutat, 2020 12;41:2143-2154). This alteration has been identified in multiple individuals diagnosed with pancreatitis (Nakano E et al. Dig Dis Sci, 2015 May;60:1297-307; Jalaly NY et al. Am J Gastroenterol, 2017 Aug;112:1320-1329). This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 11, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 17, 2024

Variant summary: CFTR c.1731C>T results in a synonymous change. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. Multiple functional studies showed that this variant has an effect on splicing, with as little as approximately 5% exon 13 inclusion (legacy name exon 12), however this effect is dependent on other neighboring variants (e.g. Raponi_2006, Pagani_2003, Amaral_2004, Fernandez Alanis_2012, Donega_2020). At-least one recent functional study reports no significant effect of this variant on splicing (Ramalho_2015). To our knowledge no studies reporting a functional impact of this variant on CFTR channel activity have been reported. The variant allele was found at a frequency of 0.00021 in 250348 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00021 vs 0.013), allowing no conclusion about variant significance. c.1731C>T has been reported in the literature in individuals affected with idiopathic chronic pancreatitis (e.g. Audrezet_2008, Nakano_2015). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. The following publications have been ascertained in the context of this evaluation (PMID: 15463919, 18687795, 32935393, 23890012, 22362925, 25492507, 15840711, 25735457, 17172597, 22591852, 26761715). ClinVar contains an entry for this variant (Variation ID: 35832). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

2.4

DANN

Benign

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over