rs200899224

Positions:

chr7-117548641-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM5PP3BS2_Supporting

The NM_000492.4(CFTR):c.1210G>C(p.Gly404Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000189 in 1,611,490 control chromosomes in the GnomAD database, including 2 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G404V) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 2 hom. )

Consequence

CFTR
NM_000492.4 missense, splice_region

Scores

Splicing: ADA: 0.9995

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 5.03

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-AS1 (HGNC:):

CFTR-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117548642-G-T is described in Lovd as [Likely_pathogenic].

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1210G>C	p.Gly404Arg	missense_variant, splice_region_variant	10/27	ENST00000003084.11	NP_000483.3
CFTR-AS1	NR_149084.1 linkuse as main transcript	n.222-6102C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1210G>C	p.Gly404Arg	missense_variant, splice_region_variant	10/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000397

AC:

AN:

151212

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000884

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000891

AC:

AN:

246874

Hom.:

AF XY:

0.0000746

AC XY:

AN XY:

134118

show subpopulations

Gnomad AFR exome

AF:

0.0000657

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:

0.000189

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000205

AC:

299

AN:

1460278

Hom.:

Cov.:

AF XY:

0.000219

AC XY:

159

AN XY:

726436

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.000264

Gnomad4 OTH exome

AF:

0.0000830

GnomAD4 genome

AF:

0.0000397

AC:

AN:

151212

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73742

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000884

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000453

ExAC

AF:

0.0000989

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 404 of the CFTR protein (p.Gly404Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 495893). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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	Johns Hopkins Genomics, Johns Hopkins University	Oct 19, 2019	This CFTR variant (rs200899224) is rare (<0.1%) in large population datasets1,2 (gnomAD: 23/278104 total alleles; 0.00827%; no homozygotes). One submitter in ClinVar classifies the clinical significance of this variant as uncertain. This variant affects the first nucleotide of exon 10 (legacy exon 9), however bioinformatics tools do not predict that this variant will have a significant affect on exon 10 splicing. This has not been confirmed experimentally, to our knowledge. Of two bioinformatics tools queried, one predicts that this amino acid substitution would be probably damaging while the second predicts it would be tolerated. The glycine residue at this position is highly conserved across the species assessed. We consider the clinical significance of c.1210G>C uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2023	The p.G404R variant (also known as c.1210G>C) is located in coding exon 10 of the CFTR gene. The glycine at codon 404 is replaced by arginine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 10. This variant was identified in a cohort of individuals undergoing CFTR sequencing; however, complete phenotype and genotype information was not provided (Ridge PG et al, 2013 Jan;3:3). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

CFTR-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 30, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	May 02, 2024	The CFTR c.1210G>C variant is predicted to result in the amino acid substitution p.Gly404Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.017% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 25, 2022

Variant summary: CFTR c.1210G>C (p.Gly404Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.9e-05 in 246874 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (8.9e-05 vs 0.013), allowing no conclusion about variant significance. c.1210G>C has been reported in the literature in a heterozygote following newborn screening (Skov_2020). This report does not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 13, 2023

The CFTR c.1210G>C; p.Gly404Arg variant (rs200899224), is reported in the literature in a cohort of individuals undergoing testing for cystic fibrosis (Ridge 2013), and in a newborn screen study (Skov 2020). This variant is also reported in ClinVar (Variation ID: 495893). It is observed in the general population with an overall allele frequency of 0.008% (23/278104 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.601). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Ridge PG et al., Miller C, Bayrak-Toydemir P, Best DH, Mao R, Swensen JJ, Lyon E, Voelkerding KV. Cystic fibrosis testing in a referral laboratory: results and lessons from a six-year period. J Clin Bioinforma. 2013 Jan 23;3(1):3. PMID: 23343000. Skov M et al. Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years. Pediatr Pulmonol. 2020 Feb;55(2):549-555. PMID: 31682332. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.19

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.57

MetaRNN

Uncertain

0.50

T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.7

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-2.1

N;N

REVEL

Uncertain

0.60

Sift

Uncertain

0.013

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.040

B;.

Vest4

0.57

MutPred

0.49

Loss of helix (P = 0.0558);.;

MVP

0.98

MPC

0.0038

ClinPred

0.17

GERP RS

4.8

Varity_R

0.53

gMVP

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

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