rs113857788

Variant names:

Your query was ambiguous. Multiple possible variants found:

Germline classification Cancer classification (beta)

Variant summary

Our verdict is . The variant received 2 ACMG points: 6P and 4B. PS3PP3_ModerateBS1

The NM_000492.4(CFTR):c.4056G>C (p.Gln1352His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000587 (AC=948) in the gnomAD database across 1,614,026 control chromosomes, including 18 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0183. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (no review stars). ClinVar reports functional evidence for this variant: "SCV000603061: expression of the variant protein in a cell line reveals a significant reduction in mature CFTR protein detected compared to wildtype (Lee 2003). PMID:12952861" and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.Q1352E: Uncertain_significance (ClinVar VariationId 1693963, 2 stars); p.Q1352E: Uncertain_significance (ClinVar VariationId 3775693, 1 star); p.Q1352H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 35882) This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Cystic fibrosis (cf).

Frequency

Genomes: 𝑓 0.00060 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 15 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:12B:4

Conservation

PhyloP100: 2.15

Publications

63 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: Myriad Women's Health, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, 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

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.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PS3

Well-established functional study supports damaging effect (PS3); SCV000603061: expression of the variant protein in a cell line reveals a significant reduction in mature CFTR protein detected compared to wildtype (Lee 2003). PMID: 12952861; SCV007097334: Expression of mature glycosylated CFTR protein and whole cell chloride currents were significantly reduced in mutant cells (PMID: 12952861);

PP3

Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

BS1

GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0183 vs gene BS1 threshold 0.015.

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.4056G>C	p.Gln1352His	missense	Exon 25 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.4056G>C	p.Gln1352His	missense	Exon 25 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.4050G>C	p.Gln1350His	missense	Exon 25 of 27	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.3969G>C	p.Gln1323His	missense	Exon 24 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.000611

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0170

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.00102

AC:

257

AN:

251226

AF XY:

0.000869

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0134

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000586

AC:

857

AN:

1461710

Hom.:

Cov.:

AF XY:

0.000575

AC XY:

418

AN XY:

727170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.0000447

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0195

AC:

773

AN:

39692

South Asian (SAS)

AF:

0.000220

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111868

Other (OTH)

AF:

0.00101

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

108

163

217

271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.000597

AC:

AN:

152316

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

AN XY:

74488

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41578

American (AMR)

AF:

0.0000654

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0166

AC:

AN:

5176

South Asian (SAS)

AF:

0.000415

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000543

Hom.:

Bravo

AF:

0.000370

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0229

AC:

2808

AN:

122702

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.00625

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.000854

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (8)

CFTR-related disorder (4)

not provided (4)

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (3)

Congenital bilateral aplasia of vas deferens from CFTR mutation (1)

Hereditary pancreatitis (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.77

MutationAssessor

Pathogenic

3.4

PhyloP100

2.1

PrimateAI

Uncertain

0.74

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.92

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Varity_R

0.94

gMVP

0.96

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

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

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

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over