NM_000492.4:c.2395C>A

Variant names:

• chr7-117592562-C-A
• rs984281283
• NM_000492.4:c.2395C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000492.4(CFTR):​c.2395C>A​(p.Gln799Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,368,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q799Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.36
• Publications: 3 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.2395C>A	p.Gln799Lys	missense	Exon 14 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2395C>A	p.Gln799Lys	missense	Exon 14 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.2395C>A	p.Gln799Lys	missense	Exon 14 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.2305C>A	p.Gln769Lys	missense	Exon 13 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 180086 AF XY: 0.0000105

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: 0.0000227

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000168 AC: 23 AN: 1368830 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 12 AN XY: 671526

African (AFR) AF: 0.00 AC: 0 AN: 30350

American (AMR) AF: 0.00 AC: 0 AN: 29208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20226

East Asian (EAS) AF: 0.00 AC: 0 AN: 38914

South Asian (SAS) AF: 0.00 AC: 0 AN: 69106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49960

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.0000215 AC: 23 AN: 1069376

Other (OTH) AF: 0.00 AC: 0 AN: 56368

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic fibrosis Uncertain:1

Jul 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2395C>A (p.Q799K) alteration is located in exon 14 (coding exon 14) of the CFTR gene. This alteration results from a C to A substitution at nucleotide position 2395, causing the glutamine (Q) at amino acid position 799 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	21
DANN	Benign	0.84
DEOGEN2	Uncertain	0.58	D
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.4
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.053	B
Vest4		0.63
MutPred		0.41		Gain of ubiquitination at Q799 (P = 0.0066)
MVP		0.99
MPC		0.0039
ClinPred		0.27	T
GERP RS		4.4
Varity_R		0.17
gMVP		0.68
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs984281283; hg19: chr7-117232616; COSMIC: COSV50134361; COSMIC: COSV50134361;