NM_000492.4:c.3205G>A

Variant names:

• chr7-117611646-G-A
• rs200321110
• NM_000492.4:c.3205G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PS3 PM1 PP2 PP5 BP4

The NM_000492.4(CFTR):​c.3205G>A​(p.Gly1069Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000136 in 1,613,472 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 Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV001180539: Functional studies demonstrated that while the p.G1069R variant in CFTR does not impact protein maturation or conductance, it does reduce the probability of channel opening (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45).; SCV005906064: "Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product." PMID:8662892; SCV000601092: Experimental studies indicate this variant induces an ion channel gating defect in the CFTR protein (PMIDs: 8662892 (1996), 22210114 (2012)).; SCV005418403: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000603016: "In vitro functional analyses demonstrate that this variant does not alter protein expression, but reduces channel function (Seibert 1996)." PMID:8662892".

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:14 U:9
• Conservation: PhyloP100: 6.85
• Publications: 52 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: Likely_pathogenic. The variant received 7 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001180539: Functional studies demonstrated that while the p.G1069R variant in CFTR does not impact protein maturation or conductance, it does reduce the probability of channel opening (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45).; SCV005906064: "Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product." PMID:8662892; SCV000601092: Experimental studies indicate this variant induces an ion channel gating defect in the CFTR protein (PMIDs: 8662892 (1996), 22210114 (2012)).; SCV005418403: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000603016: "In vitro functional analyses demonstrate that this variant does not alter protein expression, but reduces channel function (Seibert 1996)." PMID: 8662892
• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000492.4
• 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.
• PP5: Variant 7-117611646-G-A is Pathogenic according to our data. Variant chr7-117611646-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 53684.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24175769). . Strength limited to SUPPORTING due to the PP5.

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.3205G>A	p.Gly1069Arg	missense	Exon 20 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4583C>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.3205G>A	p.Gly1069Arg	missense	Exon 20 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3205G>A	p.Gly1069Arg	missense	Exon 20 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3118G>A	p.Gly1040Arg	missense	Exon 19 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 151976 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000255 AC: 64 AN: 250934 AF XY: 0.000206

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000125 AC: 183 AN: 1461378 Hom.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 94 AN XY: 726980

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.000134 AC: 6 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00113 AC: 45 AN: 39678

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86234

European-Finnish (FIN) AF: 0.000412 AC: 22 AN: 53382

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000810 AC: 90 AN: 1111750

Other (OTH) AF: 0.000133 AC: 8 AN: 60358

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152094 Hom.: 0 Cov.: 31 AF XY: 0.000282 AC XY: 21 AN XY: 74348

African (AFR) AF: 0.0000964 AC: 4 AN: 41496

American (AMR) AF: 0.0000656 AC: 1 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5160

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.000661 AC: 7 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 67996

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.000170 Hom.: 0

Bravo AF: 0.000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000231 AC: 28

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
6	3	-	Cystic fibrosis (9)
3	2	-	CFTR-related disorder (5)
1	2	-	not provided (3)
2	-	-	Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
-	1	-	Hereditary pancreatitis (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Benign	0.89
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.0072	T
MutationAssessor	Benign	1.3	L
PhyloP100		6.9
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.14	N
REVEL	Uncertain	0.60
Sift	Benign	0.48	T
Sift4G	Benign	0.094	T
Polyphen		0.77	P
Vest4		0.86
MutPred		0.93		Gain of MoRF binding (P = 0.025)
MVP		0.98
MPC		0.0038
ClinPred		0.088	T
GERP RS		4.8
PromoterAI		-0.0040	Neutral
Varity_R		0.57
gMVP		0.96
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200321110; hg19: chr7-117251700; COSMIC: COSV50043830;