rs386134230

Variant names:

• chr7-117606674-G-A
• rs386134230
• NM_000492.4:c.2909G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-117606674-G-A
• chr7-117606674-G-T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1 PM5 PP2 PP3 PP5_Very_Strong

The NM_000492.4(CFTR):​c.2909G>A​(p.Gly970Asp) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000594 in 1,515,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G970S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000059 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Pathogenic reviewed by expert panel P:16
• Conservation: PhyloP100: 6.03
• Publications: 59 publications found

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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 22 uncertain in NM_000492.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117603782-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53589.
• 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.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 7-117606674-G-A is Pathogenic according to our data. Variant chr7-117606674-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 35854.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2909G>A	p.Gly970Asp	missense_variant, splice_region_variant	Exon 18 of 27	ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.178-1685C>T		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2909G>A	p.Gly970Asp	missense_variant, splice_region_variant	Exon 18 of 27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151820 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250920 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000586 AC: 8 AN: 1364068 Hom.: 0 Cov.: 24 AF XY: 0.00000292 AC XY: 2 AN XY: 684496

African (AFR) AF: 0.00 AC: 0 AN: 31468

American (AMR) AF: 0.00 AC: 0 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25528

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39112

South Asian (SAS) AF: 0.00 AC: 0 AN: 84154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53122

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5554

European-Non Finnish (NFE) AF: 9.77e-7 AC: 1 AN: 1023280

Other (OTH) AF: 0.0000175 AC: 1 AN: 57272

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151820 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74128

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41274

American (AMR) AF: 0.00 AC: 0 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:9

Oct 25, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.2909G>A (p.Gly970Asp) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five 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 250920 control chromosomes. c.2909G>A has been reported in the literature as biallelic compound heterozygous genotypes in multiple individuals affected with Cystic Fibrosis (example, Wagner_1999, Li_2012, Goubau_2009, McCague_2019, Tian_2016). These data indicate that the variant is very likely to be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function (example, Wagner_1999, Amato_2019). The most pronounced variant effect results in 5-12% of normal CFTR channel activity and a partial trafficking defect that were both sensitive to potentiator (VX-770, Ivacaftor) or correctors (VX-809, Lumacaftor and VX-661, Tezacaftor). Seven clinical diagnostic laboratories and an expert panel (CFTR2) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jan 21, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Gly970Asp variant in CFTR has been reported in the compound heterozygous state in a least 13 individuals of predominantly Asian ancestry with CFTR-related disorders (10 with cystic fibrosis and 3 with congenital bilateral absence of the vas deferens (CBAVD); Wagner 1999, Wine 2001, Goubau 2009, Li 2012, Tian 2016, Xu 2017, Amato 2019). In at least 10 of these individuals, the second identified variant was pathogenic or likely pathogenic. This variant has also been identified in 0.016% (3/18394) of East Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). However, this frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies provide some evidence that this variant impacts protein function (Wagner 1999, Amato 2019) and computational prediction tools and conservation analyses are consistent with pathogenicity. This variant is located in the first base of the exon, which is part of the 3’ splice region. Additional computational tools do not predict altered splicing. Additionally, this variant was classified as pathogenic on August 31st, 2018 by the ClinGen-approved CFTR2 expert panel (Variation ID 35854). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM3_Very Strong, PM2, PP3, PS3_Supporting. -

Mar 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 06, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G970D pathogenic mutation (also known as c.2909G>A) is located in coding exon 18 of the CFTR gene. The glycine at codon 970 is replaced by aspartic acid, an amino acid with similar properties. This change occurs in the first base pair of coding exon 18. This mutation has been reported in multiple individuals diagnosed with cystic fibrosis and congenital bilateral absence of the vas deferens, who were described as compound heterozygotes with additional CFTR variants detected; segregation analysis confirming variants were in trans (on different chromosomes) was documented in some cases (Wagner JA et al. Hum. Genet., 1999 Jun;104:511-5; Wine JJ et al. Pediatrics, 2001 Feb;107:280-6; Li H et al. J. Cyst. Fibros., 2012 Jul;11:316-23; Liu JR et al. Zhonghua Er Ke Za Zhi, 2012 Nov;50:829-33; Xu J et al. Pediatr. Pulmonol., 2017 08;52:1020-1028; Huang T et al. Glob Pediatr Health, 2019 Apr;6:2333794X19833725; Amato F et al. Hum. Mutat., 2019 06;40:742-748). Limited functional studies demonstrated trafficking defects and decreased channel activity (Amato F et al. Hum. Mutat., 2019 06;40:742-748), and another functional analysis of this variant in CFBE cells demonstrated 48% activity compared to wild type (Raraigh KS et al. Am J Hum Genet, 2018 06;102:1062-1077). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Jun 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 970 of the CFTR protein (p.Gly970Asp). This variant is present in population databases (rs386134230, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 10453741, 22483971, 23302613, 27081564, 28608624). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 35854). 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 disruptive. Experimental studies have shown that this missense change affects CFTR function (PMID: 28608624). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Aug 31, 2018

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Jul 09, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2909G>A; p.Gly970Asp variant (rs386134230, ClinVar Variation ID: 35854) is reported in the literature in numerous individuals affected with cystic fibrosis (CF) (Goubau 2009, Tian 2016, Wagner 1999, Xu 2017, CFTR2 database). This variant has been observed in affected individuals in trans to other pathogenic variants, and it is primarily associated with pancreatic-sufficient CF (Goubau 2009, Tian 2016, Wagner 1999, CFTR2 database). Additionally, this variant has been observed in individuals with congenital bilateral absence of the vas deferens (CBAVD) (Hou 2023), including those that also carried mild pathogenic variants (Li 2012). This variant is only observed on three alleles in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.985). Consistent with this, the p.Gly970Asp variant protein exhibits 1.7% of wildtype chloride channel activity in CFBE cells (CFTR2 database) and shows decreased efflux activity in HEK cells (Wagner 1999). Additionally, other amino acid substitutions at this codon (p.Gly970Arg, p.Gly970Ser) have been reported in individuals with CF and are considered pathogenic (Ortiz 2017, Sosnay 2012, CFTR2 database). Based on available information, the p.Gly970Asp variant is considered to be pathogenic. References: CFTR2 database: https://cftr2.org Goubau C et al. Phenotypic characterisation of patients with intermediate sweat chloride values: towards validation of the European diagnostic algorithm for cystic fibrosis. Thorax. 2009 Aug;64(8):683-91. PMID: 19318346. Hou JW et al. Loss-of-function CFTR p.G970D missense mutation might cause congenital bilateral absence of the vas deferens and be associated with impaired spermatogenesis. Asian J Androl. 2023 Jan-Feb;25(1):58-65. PMID: 35665694. Li H et al. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) in Chinese patients with congenital bilateral absence of vas deferens. J Cyst Fibros. 2012 Jul;11(4):316-23. PMID: 22483971. Ortiz SC et al. Spectrum of CFTR gene mutations in Ecuadorian cystic fibrosis patients: the second report of the p.H609R mutation. Mol Genet Genomic Med. 2017 Nov;5(6):751-757. PMID: 29178639. Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. PMID: 23974870. Tian X et al. p.G970D is the most frequent CFTR mutation in Chinese patients with cystic fibrosis. Hum Genome Var. 2016 Jan 7;3:15063. PMID: 27081564. Wagner JA et al. Two novel mutations in a cystic fibrosis patient of Chinese origin. Hum Genet. 1999 Jun;104(6):511-5. PMID: 10453741. Xu J et al. Four case reports of Chinese cystic fibrosis patients and literature review. Pediatr Pulmonol. 2017 Aug;52(8):1020-1028. PMID: 28608624 -

Jan 29, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM3_STR, PM2_SUP, PM5_STR, PP3, PP4 -

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:2

-

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PP3_Strong+PM3_VeryStrong+PP4 -

not provided Pathogenic:2

Sep 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 11, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate p.G970D is functionally impaired compared to wild type (Wagner et al., 1999); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32020786, 31036917, 35314707, 22483971, 35894192, 36038301, 23302613, 10453741, 28608624, 32429104, 30420730, 33713579, 37477516, 36604502, 35665694, 32539862, 30851139, 32761997, 32777524) -

CFTR-related disorder Pathogenic:1

Mar 25, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 29, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;.;.;D;.
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H;.;.;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.9	D;.;.;D;.
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D;.;.;D;.
Sift4G	Pathogenic	0.0010	D;.;.;D;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.98
MutPred		0.96		Loss of catalytic residue at G970 (P = 0.0317);.;.;.;.;
MVP		1.0
MPC		0.015
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
Splicevardb		2.0
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 0

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

Other links and lift over

dbSNP: rs386134230; hg19: chr7-117246728;