chr7-117592427-G-C

Variant names:

• chr7-117592427-G-C
• NM_000492.4:c.2260G>C
• CFTR p.Val754Leu

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACMG Germline Pathogenicity v2019). PM1_SupportingPM2

The NM_000492.4(CFTR):c.2260G>C (p.Val754Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V754A: Uncertain_significance (ClinVar VariationId 3832578, 1 star); p.V754M: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 53465); p.V754= (synonymous): Likely_benign (ClinVar VariationId 618564, 2 stars); p.V754= (synonymous): Likely_benign (ClinVar VariationId 1788658, 1 star)

• Frequency: Genomes: not found (cov: 33)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.290
• Publications: 0 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):

• congenital bilateral aplasia of vas deferens from CFTR mutation

  Inheritance: AR Classification: DEFINITIVE Submitted by: Natera
• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Myriad Women's Health, ClinGen, Natera, 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)

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM1Mutational hot spot or critical domain		Missense neighbourhood moderate hotspot (≥2 P/LP within ±8 AA, OR ≥ 2 vs. background) — PM1 supporting; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 2 pathogenic, 4 benign (OR vs. background: 2.8).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.0119) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CFTR NM_000492.4	MANE Select	c.2260G>C p.Val754Leu	missense	Exon 14 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.2260G>Cp.Val754Leu

Exon rankExon 14 of 27

missense

Prot: NP_000483.3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CFTR ENST00000003084.11	TSL:1MANE Select	c.2260G>C p.Val754Leu	missense	Exon 14 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.2260G>C p.Val754Leu	missense	Exon 14 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.2173G>C p.Val725Leu	missense	Exon 13 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.2260G>Cp.Val754Leu

Exon rankExon 14 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.2260G>Cp.Val754Leu

Exon rankExon 14 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.2173G>Cp.Val725Leu

Exon rankExon 13 of 26

missense

Prot: ENSP00000559265.1UniProt: A0ACI8SBR8

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.34
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	0.033
DANN	Benign	0.67
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.070	N
FuncVEP CTI	Benign	0.0018
GPN-Star LLR	N/A	-3.5
GPN-Star score	N/A	3.5
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.081	T
MetaSVM	Benign	-0.47	T
Mutation Taster	N/A	100/0	polymorphism
MutationAssessor	Benign	0.64	N
PhyloP100	Benign	-0.29
popEVE	Benign	-2.8
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.16	N
REVEL	Uncertain	0.30
Sift	Benign	0.68	T
Sift4G	Benign	0.79	T
Varity_R	N/A	0.20
VESM-3B	Benign	-3.8

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.070	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

hg19: chr7-117232481;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar