NM_000492.4:c.1657C>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000492.4(CFTR):c.1657C>T(p.Arg553*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000971 in 1,606,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★). Synonymous variant affecting the same amino acid position (i.e. R553R) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000094 ( 0 hom. )

Consequence

CFTR
NM_000492.4 stop_gained

Scores

Clinical Significance

Pathogenic practice guideline P:30O:1

Conservation

PhyloP100: 1.98

Publications

349 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), Myriad Women’s Health, Laboratory for Molecular Medicine
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

ACMG classification

Classification was made for transcript

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

PVS1

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

PP5

Variant 7-117587811-C-T is Pathogenic according to our data. Variant chr7-117587811-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7122.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.1657C>T	p.Arg553*	stop_gained	Exon 12 of 27	NP_000483.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1657C>T	p.Arg553*	stop_gained	Exon 12 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.1657C>T	p.Arg553*	stop_gained	Exon 12 of 27	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.1657C>T	p.Arg553*	stop_gained	Exon 12 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.0000678

AC:

AN:

250780

AF XY:

0.0000885

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:

0.000124

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000942

AC:

137

AN:

1454226

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

724050

show subpopulations

African (AFR)

AF:

0.0000601

AC:

AN:

33266

American (AMR)

AF:

0.00

AC:

AN:

44614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26054

East Asian (EAS)

AF:

0.00

AC:

AN:

39582

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000116

AC:

128

AN:

1105364

Other (OTH)

AF:

0.0000499

AC:

AN:

60074

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

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:

0.000125

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000147

AC:

AN:

68008

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000179

Hom.:

Bravo

AF:

0.000147

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000124

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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 (16)

not provided (7)

Bronchiectasis with or without elevated sweat chloride 1 (2)

CFTR-related disorder (2)

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)

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)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.86

PhyloP100

2.0

Vest4

0.93

GERP RS

4.4

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.21

Position offset: 22

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over