chr7-117592427-G-A

Variant names:

• chr7-117592427-G-A
• rs150157202
• NM_000492.4:c.2260G>A
• CFTR p.Val754Met

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). BP6_Strong

The NM_000492.4(CFTR):c.2260G>A (p.Val754Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00191 (AC=3,074) in the gnomAD database across 1,612,184 control chromosomes, including 6 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.00204. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). 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.V754= (synonymous): Likely_benign (ClinVar VariationId 618564, 2 stars); p.V754= (synonymous): Likely_benign (ClinVar VariationId 1788658, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:16
• Conservation: PhyloP100: -0.290
• Publications: 24 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: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 0 star(s). ClinVar submissions strongly and reliably favor benignity (12/15 total B/LB).

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>A p.Val754Met	missense	Exon 14 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.2260G>Ap.Val754Met

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>A p.Val754Met	missense	Exon 14 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.2260G>A p.Val754Met	missense	Exon 14 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.2173G>A p.Val725Met	missense	Exon 13 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.2260G>Ap.Val754Met

Exon rankExon 14 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.2260G>Ap.Val754Met

Exon rankExon 14 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.2173G>Ap.Val725Met

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00171	AC:260	Hom:0	AN:152152	Cov:33
GnomAD2 exomes	AF: 0.00182	AC:453	Hom:	AN:248828	Cov:
GnomAD4 exome	AF: 0.00193	AC:2814	Hom:6	AN:1459914	Cov:32
GnomAD4 genome	AF: 0.00171	AC:260	Hom:0	AN:152270	Cov:33
TOPMed (Bravo)	AF: 0.00172	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00180	AC:652	Hom:1	AN:362558	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00470	AC:11	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00169	AC:22	Hom:	AN:13006	Cov:
Turkish Variome	AF: 0.00179	AC:12	Hom:0	AN:6720	Cov:
UK10K	AF: 0.00251	AC:19	Hom:	AN:7562	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00302 *	33	10942	0.00274 *	48	17504
BipEx(Bipolar disorder (including schizoaffective))	0.00246	70	28420	0.00201	58	28844
Epi25(Epilepsy)	0.00167	70	41958	0.00211	141	66840
SCHEMA(Schizophrenia)	0.00175	198	113172	0.00201	382	190054

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	8	not provided (10)
-	1	5	Cystic fibrosis (6)
-	-	2	not specified (2)
-	1	-	CFTR-related disorder (1)
-	-	1	Hereditary pancreatitis (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.29
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	0.17
DANN	Benign	0.15
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.046	N
GPN-Star LLR	N/A	-1.6
GPN-Star score	N/A	1.6
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.0085	T
MetaSVM	Benign	-0.35	T
Mutation Taster	N/A	100/0	polymorphism
MutationAssessor	Benign	-0.055	N
PhyloP100	Benign	-0.29
popEVE	Benign	-2.9
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.40	N
REVEL	Uncertain	0.52
Sift	Benign	0.56	T
Sift4G	Benign	0.95	T
Varity_R	N/A	0.17
VESM-3B	Benign	-4.3

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	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

dbSNP: rs150157202;

hg19: chr7-117232481;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar