rs397508784

Positions:

chr7-117535377-C-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000492.4(CFTR):c.709C>G(p.Gln237Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,994 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 7.33

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a transmembrane_region Helical; Name=4 (size 20) in uniprot entity CFTR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 7-117535377-C-G is Pathogenic according to our data. Variant chr7-117535377-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 54042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117535377-C-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.709C>G	p.Gln237Glu	missense_variant	6/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.709C>G	p.Gln237Glu	missense_variant	6/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251392

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135862

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:1Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 10, 2023	Variant summary: CFTR c.709C>G (p.Gln237Glu) results in a conservative amino acid change located in the transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251392 control chromosomes (gnomAD). c.709C>G has been reported in the literature and in multiple databases in individuals affected with Cystic Fibrosis, including multiple examples where it was found in the compound heterozygous state together with a pathogenic variant (e.g. Claustres_2000, Hubert_2004, Giardet_2007, Gaitch_2016, DeWachter_2017, Ramalho_2021, Vaidyanathan_2022); however, in two of these cases, the individual either was asymptomatic or had a mild phenotype/late disease onset (e.g. Ramhalo_2021, Mekki_2021), suggesting this variant may have varying clinical consequences. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating forskolin induced swelling (FIS) of organoids from a CF patient with the genotype F508del/Q237E, and found there was some residual CFTR function that improved with treatment with ivacaftor, however, as the variant was not examined in isolation, it does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 10923036, 28830496, 27086061, 17850636, 15463882, 33946859, 32747394, 35857025). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 12, 2024

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Sep 02, 2020

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.40

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.73

D;.;.;D;.

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.91

D;D;D;D;D

M_CAP

Pathogenic

0.77

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.86

MutationAssessor

Pathogenic

3.0

M;.;.;.;M

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.4

N;.;.;N;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.011

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.97

MutPred

0.91

Loss of MoRF binding (P = 0.0495);Loss of MoRF binding (P = 0.0495);Loss of MoRF binding (P = 0.0495);.;Loss of MoRF binding (P = 0.0495);

MVP

0.96

MPC

0.014

ClinPred

0.89

GERP RS

5.4

Varity_R

0.89

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over