CFTR p.Phe992Leu

Variant names:

• chr7-117606741-T-A
• rs758250836
• NM_000492.4:c.2976T>A
• CFTR p.Phe992Leu

Your query was ambiguous. Multiple possible variants found:

• chr7-117606741-T-A
• chr7-117606741-T-G
• chr7-117606739-T-C
• chr7-117606739-TTT-CTC
• chr7-117606739-TTT-CTA
• chr7-117606739-TTT-CTG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP2 PP3

The NM_000492.4(CFTR):​c.2976T>A​(p.Phe992Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000353 in 1,417,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F992V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 5.64
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• 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: MetaRNN computational evidence supports a deleterious effect, 0.825

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.2976T>A	p.Phe992Leu	missense	Exon 18 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.178-1752A>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.2976T>A	p.Phe992Leu	missense	Exon 18 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.2976T>A	p.Phe992Leu	missense	Exon 18 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.2889T>A	p.Phe963Leu	missense	Exon 17 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251138 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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.00000353 AC: 5 AN: 1417552 Hom.: 0 Cov.: 26 AF XY: 0.00000424 AC XY: 3 AN XY: 708296

African (AFR) AF: 0.00 AC: 0 AN: 32504

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25862

East Asian (EAS) AF: 0.00 AC: 0 AN: 39368

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85262

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53320

Middle Eastern (MID) AF: 0.000529 AC: 3 AN: 5674

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071992

Other (OTH) AF: 0.0000170 AC: 1 AN: 58932

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	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)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.087	D
MutationAssessor	Benign	1.2	L
PhyloP100		5.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.77
Sift	Benign	0.062	T
Sift4G	Pathogenic	0.0	D
Varity_R		0.82
gMVP		0.92
Mutation Taster		=12/88	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs758250836; hg19: chr7-117246795;