7-117610521-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 3P and 5B. PM1PP2BP4_StrongBS2_Supporting

The NM_000492.4(CFTR):c.2991G>C(p.Leu997Phe) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00182 in 1,611,990 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L997L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0018 ( 8 hom. )

Consequence

CFTR
NM_000492.4 missense, splice_region

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:6U:21B:3O:3

Conservation

PhyloP100: 1.65

Publications

123 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:

ENSG00000083622 (HGNC:40145):

ENSG00000083622 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 20 uncertain in NM_000492.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

BP4

Computational evidence support a benign effect (MetaRNN=0.02057156).

BS2

High Homozygotes in GnomAdExome4 at 8 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.2991G>C	p.Leu997Phe	missense splice_region	Exon 19 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.178-5532C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2991G>C	p.Leu997Phe	missense splice_region	Exon 19 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.2991G>C	p.Leu997Phe	missense splice_region	Exon 19 of 27	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.2904G>C	p.Leu968Phe	missense splice_region	Exon 18 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.00211

AC:

320

AN:

151454

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000437

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00658

Gnomad ASJ

AF:

0.00577

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00321

Gnomad NFE

AF:

0.00243

Gnomad OTH

AF:

0.00482

GnomAD2 exomes

AF:

0.00229

AC:

576

AN:

251082

AF XY:

0.00244

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00420

Gnomad ASJ exome

AF:

0.00536

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00260

Gnomad OTH exome

AF:

0.00573

GnomAD4 exome

AF:

0.00179

AC:

2617

AN:

1460462

Hom.:

Cov.:

AF XY:

0.00192

AC XY:

1398

AN XY:

726580

show subpopulations

African (AFR)

AF:

0.000359

AC:

AN:

33408

American (AMR)

AF:

0.00455

AC:

203

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00571

AC:

149

AN:

26084

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39628

South Asian (SAS)

AF:

0.00140

AC:

121

AN:

86226

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00816

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00169

AC:

1878

AN:

1111052

Other (OTH)

AF:

0.00337

AC:

203

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

112

224

336

448

560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.00211

AC:

320

AN:

151528

Hom.:

Cov.:

AF XY:

0.00212

AC XY:

157

AN XY:

73992

show subpopulations

African (AFR)

AF:

0.000436

AC:

AN:

41320

American (AMR)

AF:

0.00657

AC:

100

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00577

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00125

AC:

AN:

4790

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10338

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00243

AC:

165

AN:

67936

Other (OTH)

AF:

0.00478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

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:

0.00235

Hom.:

Bravo

AF:

0.00262

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00209

AC:

ExAC

AF:

0.00209

AC:

254

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00360

EpiControl

AF:

0.00492

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (11)

Cystic fibrosis (10)

CFTR-related disorder (5)

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)

Infertility disorder (1)

not specified (1)

Obstructive azoospermia (1)

Pancreatitis (1)

HYPERTRYPSINEMIA, NEONATAL, SUSCEPTIBILITY TO (1)

PANCREATITIS, IDIOPATHIC, SUSCEPTIBILITY TO (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.021

MetaSVM

Uncertain

0.21

MutationAssessor

Benign

1.8

PhyloP100

1.7

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.0

REVEL

Uncertain

0.63

Sift

Benign

0.053

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.95

MutPred

0.73

Loss of stability (P = 0.2182)

MVP

1.0

MPC

0.0045

ClinPred

0.029

GERP RS

2.9

Varity_R

0.61

gMVP

0.93

Mutation Taster

=41/59

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

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