NM_000492.4:c.-8G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000492.4(CFTR):c.-8G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0519 in 1,613,616 control chromosomes in the GnomAD database, including 2,457 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 175 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2282 hom. )

Consequence

CFTR
NM_000492.4 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: 0.212

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.51).

BP6

Variant 7-117480087-G-C is Benign according to our data. Variant chr7-117480087-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 93148.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117480087-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.-8G>C		5_prime_UTR_variant	Exon 1 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084 link	c.-8G>C		5_prime_UTR_variant	Exon 1 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0429

AC:

6527

AN:

152004

Hom.:

175

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00971

Gnomad AMI

AF:

0.0736

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0288

Gnomad EAS

AF:

0.0605

Gnomad SAS

AF:

0.0154

Gnomad FIN

AF:

0.0975

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0601

Gnomad OTH

AF:

0.0320

GnomAD3 exomes

AF:

0.0457

AC:

11486

AN:

251068

Hom.:

364

AF XY:

0.0455

AC XY:

6176

AN XY:

135710

show subpopulations

Gnomad AFR exome

AF:

0.00802

Gnomad AMR exome

AF:

0.0185

Gnomad ASJ exome

AF:

0.0326

Gnomad EAS exome

AF:

0.0620

Gnomad SAS exome

AF:

0.0149

Gnomad FIN exome

AF:

0.0958

Gnomad NFE exome

AF:

0.0565

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0528

AC:

77166

AN:

1461494

Hom.:

2282

Cov.:

AF XY:

0.0519

AC XY:

37759

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.00726

Gnomad4 AMR exome

AF:

0.0198

Gnomad4 ASJ exome

AF:

0.0323

Gnomad4 EAS exome

AF:

0.0583

Gnomad4 SAS exome

AF:

0.0145

Gnomad4 FIN exome

AF:

0.0903

Gnomad4 NFE exome

AF:

0.0575

Gnomad4 OTH exome

AF:

0.0465

GnomAD4 genome

AF:

0.0429

AC:

6529

AN:

152122

Hom.:

175

Cov.:

AF XY:

0.0443

AC XY:

3293

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00968

Gnomad4 AMR

AF:

0.0252

Gnomad4 ASJ

AF:

0.0288

Gnomad4 EAS

AF:

0.0607

Gnomad4 SAS

AF:

0.0154

Gnomad4 FIN

AF:

0.0975

Gnomad4 NFE

AF:

0.0601

Gnomad4 OTH

AF:

0.0326

Alfa

AF:

0.0540

Hom.:

Bravo

AF:

0.0368

Asia WGS

AF:

0.0310

AC:

109

AN:

3478

EpiCase

AF:

0.0514

EpiControl

AF:

0.0444

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Jul 06, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

-8G>C in exon 1 of CFTR: This variant is not expected to have clinical significa nce because it has been identified in 5.5% (477/8600) of European American chrom osomes from a broad population by the NHLBI Exome Sequencing Project (http://evs .gs.washington. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Cystic fibrosis

Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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: BS1, BS2, BS3 -

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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 29, 2018

CFTR-France

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

the variant does not result in CFTR-RD neither -

not provided

Benign:3

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30296588, 19652440, 27022295, 15905293) -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CFTR-related disorder

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

May 10, 2017

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary pancreatitis

Benign:1

Jan 30, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.92

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

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