7-117592588-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4_StrongBS2_Supporting

The NM_000492.4(CFTR):c.2421A>G(p.Ile807Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000905 in 1,527,860 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I807T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00096 ( 7 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:7B:11

Conservation

PhyloP100: 0.357

Publications

34 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: Likely_benign. The variant received -4 ACMG points.

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=0.015308082).

BS2

High Homozygotes in GnomAdExome4 at 7 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.2421A>G	p.Ile807Met	missense	Exon 14 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.2421A>G	p.Ile807Met	missense	Exon 14 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699602.1		c.2421A>G	p.Ile807Met	missense	Exon 14 of 27	ENSP00000514471.1	A0A8V8TNH2
CFTR	ENST00000889206.1		c.2334A>G	p.Ile778Met	missense	Exon 13 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes

AF:

0.000440

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000774

AC:

139

AN:

179550

AF XY:

0.000970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000251

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000623

Gnomad OTH exome

AF:

0.000486

GnomAD4 exome

AF:

0.000955

AC:

1314

AN:

1375492

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

737

AN XY:

677592

show subpopulations

African (AFR)

AF:

0.0000328

AC:

AN:

30444

American (AMR)

AF:

0.000246

AC:

AN:

28430

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20368

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39112

South Asian (SAS)

AF:

0.00596

AC:

407

AN:

68312

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50002

Middle Eastern (MID)

AF:

0.00187

AC:

AN:

5348

European-Non Finnish (NFE)

AF:

0.000778

AC:

838

AN:

1076684

Other (OTH)

AF:

0.000880

AC:

AN:

56792

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

153

230

306

383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

108

144

180

<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:

0.000446

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.0000721

AC:

AN:

41594

American (AMR)

AF:

0.000131

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00393

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68038

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000719

Hom.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000877

AC:

106

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (7)

not provided (7)

CFTR-related disorder (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)

Hereditary pancreatitis (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Benign

0.0061

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.73

MutationAssessor

Uncertain

2.3

PhyloP100

0.36

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.1

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.80

MVP

1.0

MPC

0.0060

ClinPred

0.15

GERP RS

-4.5

Varity_R

0.42

gMVP

0.69

Mutation Taster

=55/45

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