chr7-117540120-G-A

Variant names:

• chr7-117540120-G-A
• rs143486492
• NM_000492.4:c.890G>A
• CFTR p.Arg297Gln

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PP3BP6

The NM_000492.4(CFTR):c.890G>A (p.Arg297Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000885 (AC=1,427) in the gnomAD database across 1,613,130 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00107. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. 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.R297= (synonymous): Likely_benign (ClinVar VariationId 1765115, 1 star); p.R297= (synonymous): Likely_benign (ClinVar VariationId 4843833, 1 star); p.R297W: Uncertain_significance (ClinVar VariationId 54080, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:9
• Conservation: PhyloP100: 6.39
• Publications: 13 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 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — supporting evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Supporting).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).

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.890G>A p.Arg297Gln	missense	Exon 8 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.890G>Ap.Arg297Gln

Exon rankExon 8 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.890G>A p.Arg297Gln	missense	Exon 8 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.890G>A p.Arg297Gln	missense	Exon 8 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.890G>A p.Arg297Gln	missense	Exon 8 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.890G>Ap.Arg297Gln

Exon rankExon 8 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.890G>Ap.Arg297Gln

Exon rankExon 8 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.890G>Ap.Arg297Gln

Exon rankExon 8 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: 0.000677	AC:103	Hom:1	AN:152058	Cov:32
GnomAD2 exomes	AF: 0.000567	AC:142	Hom:	AN:250572	Cov:
GnomAD4 exome	AF: 0.000907	AC:1325	Hom:0	AN:1460952	Cov:30
GnomAD4 genome	AF: 0.000670	AC:102	Hom:0	AN:152178	Cov:32
TOPMed (Bravo)	AF: 0.000552	AC:146	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000907	AC:213	Hom:0	AN:234820	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.000443	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00131	AC:17	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.00289	AC:10	Hom:	AN:3478	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000240	AC:3	Hom:0	AN:122692	Cov:
Turkish Variome	AF: 0.00104	AC:7	Hom:0	AN:6718	Cov:
UK10K	AF: 0.000132	AC:1	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000223	AC:2	Hom:0	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000451 *	5	11078	0.000455 *	8	17568
BipEx(Bipolar disorder (including schizoaffective))	0.000915	26	28418	0.000728	21	28838
Epi25(Epilepsy)	0.000644	27	41956	0.000957	64	66884
SCHEMA(Schizophrenia)	0.000525	64	121906	0.000582	111	190710

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
-	5	4	Cystic fibrosis (9)
-	5	1	not provided (6)
-	-	3	not specified (3)
-	-	1	CFTR-related disorder (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Benign	0.052
GPN-Star LLR	N/A	-5.5
GPN-Star score	N/A	5.3
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.35	D
Mutation Taster	N/A	8/92	disease causing
MutationAssessor	Uncertain	2.1	M
PhyloP100	Uncertain	6.4
popEVE	Benign	-3.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.038	D
Varity_R	N/A	0.72
VESM-3B	Benign	-6.5

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.050
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: rs143486492;

hg19: chr7-117180174;

COSMIC: COSV99133519;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar