chr7-117504291-G-T

Position:

chr7-117504291-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000492.4(CFTR):c.92G>T(p.Arg31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000874 in 1,612,452 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R31C) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:11O:1

Conservation

PhyloP100: 1.90

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:

CFTR (HGNC:):

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 76) in uniprot entity CFTR_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2548123).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.92G>T	p.Arg31Leu	missense_variant	2/27	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.92G>T	p.Arg31Leu	missense_variant	2/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000319

AC:

AN:

250924

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135608

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000530

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000883

AC:

129

AN:

1460396

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726678

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000106

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152056

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74260

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000668

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:11Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 29, 2022	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 31 of the CFTR protein (p.Arg31Leu). This variant is present in population databases (rs149353983, gnomAD 0.008%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 12454843). ClinVar contains an entry for this variant (Variation ID: 54087). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CFTR function (PMID: 16339147). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 13, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 29, 2024	The p.R31L variant (also known as c.92G>T), located in coding exon 2 of the CFTR gene, results from a G to T substitution at nucleotide position 92. The arginine at codon 31 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been detected in an individual with elevated sweat chloride levels and virtually normal pulmonary and pancreatic function; however, no second CFTR alteration was identified (Zielenski J, Hum. Mutat. 1995; 5(1):43-7). In vitro protein studies show that this alteration causes a reduction in the surface expression of the CFTR protein (Jurkuvenaite A, J. Biol. Chem. 2006 Feb; 281(6):3329-34; Raraigh KS et al. Am. J. Hum. Genet., 2018 06;102:1062-1077). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 01, 2019	This variant has been previously reported in patients with a phenotypic consistent with cystic fibrosis and is currently classified as a variant of uncertain significance by three submitters in ClinVar. Functional studies have shown that this variant may lead to reduced protein function, however the impact of this variant is not completely understood at this time. Additionally, this CFTR variant (rs149353983) is rare (<0.1%) in large population datasets (gnomAD: 11/282294 total alleles; 0.0039%; no homozygotes). Two bioinformatic tools queried predict that this substitution would be tolerated, and the arginine residue at this position is evolutionarily conserved across most species assessed. The clinical significance of c.92G>T is uncertain at this time. -
Uncertain significance, reviewed by expert panel	research	CFTR2	Mar 03, 2017	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2018	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 11, 2024

Variant summary: CFTR c.92G>T (p.Arg31Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251968 control chromosomes. c.92G>T has been reported in the literature as a heterozygous non-informative genotype (second allele not specified) in a 24 year old initially reported with pulmonary symptoms at age 5.7 years but virtually normal pulmonary and pancreatic functions at age 24 despite an elevated sweat chloride level (90.8 mmol/L) (example, Zielenski_1995); in compound heterozygosity with p.F508del in at-least 7 individuals with a mean sweat chloride level of 37 mmol/L in the CFTR-2 database (example, McCague_2019, Munck_2020); a non-informative genotype in the South African CF registry (SACFR) (example, Zampoli_2021). These data do not allow any conclusion about variant significance. At least three publications report conflicting experimental evidence evaluating an impact on protein function in-vitro (example, Jurkuvenalte_2006, Raraigh_2018, Bihler_2024). The most pronounced variant effect results in diminished channel activity compared to wild-type (<10% of WT) in one study (Jurkuvenalte_2006), an indeterminate level of channel activity (56% of WT) in another (Raraigh_2018) and approximately (Gt channel conductance) 22% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 18193900, 17098864, 18306312, 17235394, 17098482, 7526685, 16251901, 31036917, 38388235, 16339147, 30888834, 15536480, 31916691, 29805046, 34996830, 34583889, 34350279, 7537150). ClinVar contains an entry for this variant (Variation ID: 54087). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Lung disease, non-specific

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Jun 17, 2015

- -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

Apr 30, 2021

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;.;.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.25

T;T;T;T;T

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

1.8

L;.;.;.;L

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

N;.;.;N;.

REVEL

Uncertain

0.55

Sift

Benign

0.11

T;.;.;T;.

Sift4G

Uncertain

0.0080

D;.;.;D;.

Polyphen

0.33

B;.;.;.;.

Vest4

0.89

MVP

0.99

MPC

0.0043

ClinPred

0.091

GERP RS

1.9

Varity_R

0.27

gMVP

0.76

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

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