rs1800130

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000492.4(CFTR):c.3870A>G(p.Pro1290Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0416 in 1,613,132 control chromosomes in the GnomAD database, including 2,219 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1290P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.071 ( 601 hom., cov: 33)

Exomes 𝑓: 0.038 ( 1618 hom. )

Consequence

CFTR
NM_000492.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16O:1

Conservation

PhyloP100: -0.238

Publications

37 publications found

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 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)

CFTR links:

ENSG00000083622 (HGNC:40145):

ENSG00000083622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.64).

BP6

Variant 7-117642590-A-G is Benign according to our data. Variant chr7-117642590-A-G is described in ClinVar as Benign. ClinVar VariationId is 93153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.238 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.3870A>G	p.Pro1290Pro	synonymous_variant	Exon 23 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS2	NR_199597.1 link	n.65+4761T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.3870A>G	p.Pro1290Pro	synonymous_variant	Exon 23 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0712

AC:

10828

AN:

152112

Hom.:

592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.0647

Gnomad AMR

AF:

0.0295

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.00462

Gnomad SAS

AF:

0.0522

Gnomad FIN

AF:

0.127

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0341

Gnomad OTH

AF:

0.0598

GnomAD2 exomes

AF:

0.0483

AC:

12102

AN:

250546

AF XY:

0.0474

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.0195

Gnomad ASJ exome

AF:

0.0278

Gnomad EAS exome

AF:

0.00285

Gnomad FIN exome

AF:

0.125

Gnomad NFE exome

AF:

0.0354

Gnomad OTH exome

AF:

0.0422

GnomAD4 exome

AF:

0.0385

AC:

56204

AN:

1460904

Hom.:

1618

Cov.:

AF XY:

0.0386

AC XY:

28068

AN XY:

726730

show subpopulations

African (AFR)

AF:

0.154

AC:

5164

AN:

33430

American (AMR)

AF:

0.0207

AC:

925

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.0304

AC:

794

AN:

26098

East Asian (EAS)

AF:

0.00473

AC:

187

AN:

39564

South Asian (SAS)

AF:

0.0547

AC:

4718

AN:

86232

European-Finnish (FIN)

AF:

0.119

AC:

6341

AN:

53384

Middle Eastern (MID)

AF:

0.0548

AC:

316

AN:

5762

European-Non Finnish (NFE)

AF:

0.0318

AC:

35306

AN:

1111444

Other (OTH)

AF:

0.0406

AC:

2453

AN:

60352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

2744

5488

8231

10975

13719

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1384

2768

4152

5536

6920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0715

AC:

10879

AN:

152228

Hom.:

601

Cov.:

AF XY:

0.0744

AC XY:

5541

AN XY:

74434

show subpopulations

African (AFR)

AF:

0.149

AC:

6171

AN:

41536

American (AMR)

AF:

0.0295

AC:

450

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0294

AC:

102

AN:

3470

East Asian (EAS)

AF:

0.00463

AC:

AN:

5184

South Asian (SAS)

AF:

0.0520

AC:

251

AN:

4824

European-Finnish (FIN)

AF:

0.127

AC:

1352

AN:

10604

Middle Eastern (MID)

AF:

0.0476

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0341

AC:

2319

AN:

68016

Other (OTH)

AF:

0.0649

AC:

137

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

494

988

1481

1975

2469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

256

384

512

640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0440

Hom.:

863

Bravo

AF:

0.0663

Asia WGS

AF:

0.0660

AC:

231

AN:

3478

EpiCase

AF:

0.0288

EpiControl

AF:

0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Benign:6

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. -

Aug 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2020

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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 -

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 3 unrelated patients 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: BA1, BS1 -

not specified

Benign:4

Jul 16, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Pro1290Pro in exon 23 of CFTR: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 15.1% (665/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800130). -

CFTR-related disorder

Benign:3

Aug 31, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 29, 2017

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 20, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 10572229, 24631642, 25033378, 23503723, 10601093, 22483971, 26436105, 27488005, 27022295, 28456595) -

Hereditary pancreatitis

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.6

(source)

DANN

Benign

0.62

PhyloP100

-0.24

Mutation Taster

=87/13

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over