NM_000492.4:c.2909G>A

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 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 (★★★). ClinVar reports functional evidence for this variant: "SCV000052160: 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).; SCV000245589: In vitro functional studies provide some evidence that this variant impacts protein function (Wagner 1999, Amato 2019); SCV001160438: 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). PMID:10453741; SCV001585849: Experimental studies have shown that this missense change affects CFTR function (PMID:28608624).; SCV002750948: 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).; SCV005201951: Published functional studies demonstrate p.G970D is functionally impaired compared to wild type (Wagner et al., 1999);". 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: 61 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: 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000052160: 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).; SCV000245589: In vitro functional studies provide some evidence that this variant impacts protein function (Wagner 1999, Amato 2019); SCV001160438: 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). PMID: 10453741; SCV001585849: Experimental studies have shown that this missense change affects CFTR function (PMID: 28608624).; SCV002750948: 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).; SCV005201951: Published functional studies demonstrate p.G970D is functionally impaired compared to wild type (Wagner et al., 1999)
• 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.

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.2909G>A	p.Gly970Asp	missense splice_region	Exon 18 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.178-1685C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2909G>A	p.Gly970Asp	missense splice_region	Exon 18 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.2909G>A	p.Gly970Asp	missense splice_region	Exon 18 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.2822G>A	p.Gly941Asp	missense splice_region	Exon 17 of 26	ENSP00000559265.1

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

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
9	-	-	Cystic fibrosis (9)
2	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
2	-	-	not provided (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	CFTR-related disorder (1)
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)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		6.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	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;