rs80224560

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.2657+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000782 in 1,610,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★★). ClinVar reports functional evidence for this variant: "SCV000603041: Functional studies reveal that the variant leads to the production of an aberrant transcript, while reducing full-length transcripts to 4% of normal levels (Highsmith 1997). PMID:9101293" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000078 ( 1 hom. )

Consequence

CFTR
NM_000492.4 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic practice guideline P:34O:1

Conservation

PhyloP100: 5.83

Publications

74 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: Orphanet, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Myriad Women's Health
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:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000492.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000603041: Functional studies reveal that the variant leads to the production of an aberrant transcript, while reducing full-length transcripts to 4% of normal levels (Highsmith 1997). PMID: 9101293; SCV000967659: RNA studies have shown that the c.2657+5G>A causes aberrant splicing, resulting in the skipping of exons 15 and 16 and leading to a significantly decreased expression of CFTR (Masvidal 2014, Sharma 2014).; SCV001177160: An in vitro minigene assay had concordant findings and showed that this mutation reduces protein expression to <10% of wild type (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7).; SCV001586033: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24129438, 25066652).; SCV003921835: Mini gene assays and ex vivo studies demonstrated that the variant results in the skipping of exon 16 (PMID: 24129438). (SP); SCV000567676: Functional studies have shown that c.2657+5G>A causes aberrant splicing and results in the skipping of exon 16. Also, very low levels of CFTR are expressed in mutant cell lines (Masvidal et al., 2014; Sharma et al., 2014).; SCV004221677: Functional studies have described this variant as a Class V variant, causing aberrant splicing, exon 16 skipping, and partial loss of the CFTR protein (PMIDs: 9101293 (1997), 24129438 (2014), 25066652 (2014)).; SCV000919153: At least one publication reports experimental evidence that this variant affects mRNA splicing.; SCV005361750: "This variant (also known as 2789+5G>A in the literature) is predicted and functionally proven to result in aberrant splicing and skipping of exon 16 due to disruption of the splice donor site (Masvidal et al. 2014. PubMed ID: 24129438)."

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 7-117602868-G-A is Pathogenic according to our data. Variant chr7-117602868-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38497.Status of the report is practice_guideline, 4 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.2657+5G>A		splice_region intron	N/A	NP_000483.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2657+5G>A	splice_region intron	N/A	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.2657+5G>A	splice_region intron	N/A	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.2570+5G>A	splice_region intron	N/A	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152174

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:

0.000176

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000756

AC:

AN:

251474

AF XY:

0.0000809

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:

0.000158

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000782

AC:

114

AN:

1458108

Hom.:

Cov.:

AF XY:

0.0000758

AC XY:

AN XY:

725668

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33414

American (AMR)

AF:

0.0000224

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000911

AC:

101

AN:

1108564

Other (OTH)

AF:

0.000116

AC:

AN:

60270

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000789

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000978

Hom.:

Bravo

AF:

0.0000793

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:practice guideline

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (17)

not provided (9)

CFTR-related disorder (2)

Bronchiectasis with or without elevated sweat chloride 1 (1)

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (1)

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)

Cystic fibrosis;C5924204:CFTR-related disorder (1)

Hereditary pancreatitis (1)

not specified (1)

Respiratory ciliopathies including non-CF bronchiectasis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Uncertain

(source)

DANN

Benign

0.91

PhyloP100

5.8

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

Splicevardb

3.0

SpliceAI score (max)

0.93

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.93

Position offset: -5

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over