rs1800073

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4_StrongBP6BS2_Supporting

The NM_000492.4(CFTR):c.91C>T(p.Arg31Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,611,884 control chromosomes in the GnomAD database, including 9 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. R31L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 9 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:9

Conservation

PhyloP100: 3.04

Publications

51 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 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=0.011254132).

BP6

Variant 7-117504290-C-T is Benign according to our data. Variant chr7-117504290-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35893.

BS2

High Homozygotes in GnomAdExome4 at 9 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.91C>T	p.Arg31Cys	missense	Exon 2 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.91C>T	p.Arg31Cys	missense	Exon 2 of 27	ENSP00000003084.6	P13569-1
CFTR	ENST00000546407.1	TSL:1	n.204C>T		non_coding_transcript_exon	Exon 3 of 3
CFTR	ENST00000699602.1		c.91C>T	p.Arg31Cys	missense	Exon 2 of 27	ENSP00000514471.1	A0A8V8TNH2

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.0138

Gnomad EAS

AF:

0.00482

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00122

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00168

AC:

421

AN:

250938

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.0105

Gnomad EAS exome

AF:

0.00544

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00150

Gnomad OTH exome

AF:

0.00213

GnomAD4 exome

AF:

0.00154

AC:

2241

AN:

1459662

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1112

AN XY:

726340

show subpopulations

African (AFR)

AF:

0.000389

AC:

AN:

33446

American (AMR)

AF:

0.000447

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.0119

AC:

311

AN:

26098

East Asian (EAS)

AF:

0.00702

AC:

278

AN:

39622

South Asian (SAS)

AF:

0.000464

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00382

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00129

AC:

1435

AN:

1110118

Other (OTH)

AF:

0.00197

AC:

119

AN:

60298

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

199

298

398

497

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:

0.00125

AC:

190

AN:

152222

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.000361

AC:

AN:

41542

American (AMR)

AF:

0.000458

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0138

AC:

AN:

3472

East Asian (EAS)

AF:

0.00483

AC:

AN:

5178

South Asian (SAS)

AF:

0.00104

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00122

AC:

AN:

67998

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00160

Hom.:

Bravo

AF:

0.00133

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.00167

AC:

203

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00190

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Cystic fibrosis (8)

not provided (4)

not specified (3)

CFTR-related disorder (1)

Congenital bilateral aplasia of vas deferens from CFTR mutation (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)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.011

MetaSVM

Uncertain

0.75

MutationAssessor

Benign

1.8

PhyloP100

3.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.8

REVEL

Pathogenic

0.67

Sift

Uncertain

0.012

Sift4G

Pathogenic

0.0010

Polyphen

0.99

Vest4

0.89

MVP

0.99

MPC

0.0038

ClinPred

0.031

GERP RS

5.7

Varity_R

0.23

gMVP

0.77

Mutation Taster

=65/35

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