7-117509089-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 5P and 8B. PM1PM5PP2BP4_StrongBS2

The NM_000492.4(CFTR):c.220C>T(p.Arg74Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000929 in 1,612,848 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R74Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0042 ( 6 hom., cov: 33)

Exomes 𝑓: 0.00059 ( 4 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:7U:10B:5O:1

Conservation

PhyloP100: 0.911

Publications

98 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 -3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 26 uncertain in NM_000492.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117509090-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1706004.Status of the report is criteria_provided_single_submitter, 1 stars.

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=0.011099517).

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

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.220C>T	p.Arg74Trp	missense	Exon 3 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.220C>T	p.Arg74Trp	missense	Exon 3 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000699605.1		c.-24C>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 27	ENSP00000514473.1	A0A8V8TPV6
CFTR	ENST00000673785.1		c.-24C>T		5_prime_UTR_premature_start_codon_gain	Exon 6 of 13	ENSP00000501235.1	A0A669KBE8

Frequencies

GnomAD3 genomes

AF:

0.00417

AC:

634

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0126

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00478

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00103

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00528

GnomAD2 exomes

AF:

0.00149

AC:

375

AN:

250978

AF XY:

0.00111

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000652

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000335

Gnomad OTH exome

AF:

0.00131

GnomAD4 exome

AF:

0.000592

AC:

865

AN:

1460586

Hom.:

Cov.:

AF XY:

0.000533

AC XY:

387

AN XY:

726726

show subpopulations

African (AFR)

AF:

0.0125

AC:

419

AN:

33442

American (AMR)

AF:

0.00199

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26122

East Asian (EAS)

AF:

0.000126

AC:

AN:

39656

South Asian (SAS)

AF:

0.000754

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53152

Middle Eastern (MID)

AF:

0.00191

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.000167

AC:

186

AN:

1111170

Other (OTH)

AF:

0.00148

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

134

179

224

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:

0.00416

AC:

633

AN:

152262

Hom.:

Cov.:

AF XY:

0.00392

AC XY:

292

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0125

AC:

521

AN:

41560

American (AMR)

AF:

0.00477

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00135

AC:

AN:

5184

South Asian (SAS)

AF:

0.00104

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000221

AC:

AN:

68008

Other (OTH)

AF:

0.00522

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

145

181

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:

0.00141

Hom.:

Bravo

AF:

0.00548

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0123

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00172

AC:

209

Asia WGS

AF:

0.00145

AC:

AN:

3474

EpiCase

AF:

0.000491

EpiControl

AF:

0.000415

ClinVar

ClinVar submissions

Significance:drug response

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (10)

not provided (6)

not specified (3)

CFTR-related disorder (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)

Hereditary pancreatitis (1)

ivacaftor response - Efficacy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.72

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.32

MutationAssessor

Benign

0.95

PhyloP100

0.91

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.23

REVEL

Uncertain

0.48

Sift

Benign

0.065

Sift4G

Uncertain

0.0050

Polyphen

0.97

Vest4

0.73

MVP

0.97

MPC

0.0040

ClinPred

0.023

GERP RS

4.8

Varity_R

0.28

gMVP

0.93

Mutation Taster

=67/33

polymorphism

(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