7-117592412-C-T

Variant names:

• chr7-117592412-C-T
• rs151235408
• NM_000492.4:c.2245C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000492.4(CFTR):​c.2245C>T​(p.Leu749Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,613,358 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 2.63
• Publications: 7 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 7-117592412-C-T is Benign according to our data. Variant chr7-117592412-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 256251.
• BP7: Synonymous conserved (PhyloP=2.63 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.2245C>T	p.Leu749Leu	synonymous	Exon 14 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2245C>T	p.Leu749Leu	synonymous	Exon 14 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.2245C>T	p.Leu749Leu	synonymous	Exon 14 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.2155C>T	p.Leu719Leu	synonymous	Exon 13 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000611 AC: 153 AN: 250314 AF XY: 0.000643

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000465

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000760 AC: 1111 AN: 1461050 Hom.: 1 Cov.: 32 AF XY: 0.000776 AC XY: 564 AN XY: 726814

African (AFR) AF: 0.0000897 AC: 3 AN: 33456

American (AMR) AF: 0.000403 AC: 18 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.000422 AC: 11 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86144

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53384

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5766

European-Non Finnish (NFE) AF: 0.000930 AC: 1034 AN: 1111590

Other (OTH) AF: 0.000563 AC: 34 AN: 60342

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74472

African (AFR) AF: 0.000192 AC: 8 AN: 41578

American (AMR) AF: 0.0000654 AC: 1 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68018

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000852 Hom.: 0

Bravo AF: 0.000529

EpiCase AF: 0.00175

EpiControl AF: 0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:5

Apr 20, 2016

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant affects a conserved nucleotide and results in a synonymous mutation. 5/5 in silico tools predict the variant not to have an impact on splicing while mutation taster predicts the variant to be disease causing. It was predominantly observed in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.096% which does not exceed the maximal expected allele frequency of a disease causing CFTR allele (1.3%). It has been reported in patients with wide spectrum of CFTR-related disorders (CF, CBAVD, asthma and COPD) as well as in healthy population and often reported as polymorphism. In one CBAVD patient, this variant was found in cis with R764X (Pallares-Ruiz_1999). In addition, according to Bombieri, it does not lead to exon skipping, suggesting it is indeed not pathogenic. Considering all evidence, the variant was classified as Likely Benign.

Jan 30, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMIDs: 24782259 (2021) and 7689013 (1993)), emphysema (PMID: 9921909 (1998)), and congenital bilateral absence of the vas deferens (CBAVD) and oligoasthenoteratozoospermia (OAT) (PMID: 10601093 (1999)). 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.

Aug 14, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 10, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: BP4, BP7

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cystic fibrosis Benign:5

Feb 28, 2020

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 11, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 30, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR-related disorder Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Obstructive azoospermia Benign:1

Dec 21, 2021

Institute of Reproductive Genetics, University of Münster

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary pancreatitis Benign:1

Jan 10, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.1
DANN	Benign	0.44
PhyloP100		2.6
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs151235408; hg19: chr7-117232466;