rs397508192

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000492.4(CFTR):c.1340delA(p.Lys447ArgfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. K447K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CFTR
NM_000492.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:10

Conservation

PhyloP100: 2.98

Publications

5 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 links:

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117548769-CA-C is Pathogenic according to our data. Variant chr7-117548769-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 53233.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1340delA	p.Lys447ArgfsTer2	frameshift_variant	Exon 10 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730
CFTR-AS1	NR_149084.1 link	n.222-6231delT		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.1340delA	p.Lys447ArgfsTer2	frameshift_variant	Exon 10 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000412

AC:

AN:

242968

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000919

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.85e-7

AC:

AN:

1460410

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726446

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33430

American (AMR)

AF:

0.00

AC:

AN:

44610

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53256

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111200

Other (OTH)

AF:

0.00

AC:

AN:

60274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41434

American (AMR)

AF:

0.00

AC:

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Lys447Argfs*2) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 19447078, 23974870, 26574590). ClinVar contains an entry for this variant (Variation ID: 53233). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Mar 17, 2017

CFTR2

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:research

- -

Dec 17, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Previously reported disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -

Feb 04, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1340delA pathogenic mutation, located in coding exon 10 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 1340, causing a translational frameshift with a predicted alternate stop codon (p.K447Rfs*2). This alteration has been identified in multiple individuals with cystic fibrosis with a second CFTR variant (Andrew et al. Cystic Fibrosis Mutation Database [database online] Toronto, ON, Canada: SickKids;1999; Mott LS et al. J Cyst Fibros, 2009 Jul;8:285-7). In another study, this mutation was identified in 2 affected individuals in a cohort study of Celtic origin. Individuals in the cohort had a sweat chloride test result above 60 mmol/L and/or Pseudomonas colonization of the lungs (Scotet V et al. Human Mutat. 2003;22(1):105). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Mar 14, 2016

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jan 18, 2016

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Pathogenic:1

Jun 19, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CFTR c.1340delA; p.Lys447fs variant (rs397508192) is reported in the literature in multiple individuals affected with cystic fibrosis (Mott 2009, CFTR2 database). At least one affected individual with this variant was observed to carry a second pathogenic CFTR variant (Mott 2009). This variant is found on a single chromosome (1/242968 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Mott LS et al. Bronchiectasis in an asymptomatic infant with cystic fibrosis diagnosed following newborn screening. J Cyst Fibros. 2009 Jul;8(4):285-7. -

CFTR-related disorder

Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Oct 12, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.0

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over