CFTR p.Leu967Ser

Variant names:

• chr7-117603774-T-C
• rs1800110
• NM_000492.4:c.2900T>C
• CFTR p.Leu967Ser

Your query was ambiguous. Multiple possible variants found:

• chr7-117603774-T-C
• chr7-117603774-TG-CA
• chr7-117603774-TG-CC
• chr7-117603774-TG-CT
• chr7-117603773-TTG-AGC
• chr7-117603773-TTG-AGT

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACMG Germline Pathogenicity v2019). PS3PP3

The NM_000492.4(CFTR):c.2900T>C (p.Leu967Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00135 (AC=2,180) in the gnomAD database across 1,613,804 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.0016. 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 Uncertain Significance (no review stars). ClinVar reports functional evidence for this variant: "SCV000603067: Functional assays suggest this variant has a modest or no effect on chloride channel activity, but exhibits decreased bicarbonate transport (LaRusch 2014, Raraigh 2018). PMID:25033378 PMID:29805046". Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.L967= (synonymous): Likely_benign (ClinVar VariationId 495916, 2 stars); p.L967= (synonymous): Likely_benign (ClinVar VariationId 2729011, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:24 O:1
• Conservation: PhyloP100: 4.04
• Publications: 45 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 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000603067: Functional assays suggest this variant has a modest or no effect on chloride channel activity, but exhibits decreased bicarbonate transport (LaRusch 2014, Raraigh 2018). PMID: 25033378 PMID: 29805046
	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).

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.2900T>C p.Leu967Ser	missense	Exon 17 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.2900T>Cp.Leu967Ser

Exon rankExon 17 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.2900T>C p.Leu967Ser	missense	Exon 17 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.2900T>C p.Leu967Ser	missense	Exon 17 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.2813T>C p.Leu938Ser	missense	Exon 16 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.2900T>Cp.Leu967Ser

Exon rankExon 17 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.2900T>Cp.Leu967Ser

Exon rankExon 17 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.2813T>Cp.Leu938Ser

Exon rankExon 16 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: 0.00104	AC:158	Hom:0	AN:152190	Cov:33
GnomAD2 exomes	AF: 0.000721	AC:181	Hom:	AN:251214	Cov:
GnomAD4 exome	AF: 0.00138	AC:2022	Hom:1	AN:1461496	Cov:32
GnomAD4 genome	AF: 0.00104	AC:158	Hom:0	AN:152308	Cov:33
TOPMed (Bravo)	AF: 0.00104	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00121	AC:603	Hom:2	AN:500378	Cov:
Local & regional cohorts 5 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00214	AC:5	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000384	AC:5	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5162	Cov:
UK10K	AF: 0.00145	AC:11	Hom:	AN:7562	Cov:

Showing 11 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000900 *	10	11112	0.000511 *	9	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00144	41	28420	0.00159	46	28844
Epi25(Epilepsy)	0.00131	55	41956	0.00161	108	66878
SCHEMA(Schizophrenia)	0.000887	108	121732	0.000834	159	190620

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
4	6	-	Cystic fibrosis (10)
-	10	-	not provided (10)
-	3	-	CFTR-related disorder (3)
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 (2)
-	1	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	1	-	Hereditary pancreatitis (1)
-	1	-	Infertility disorder (1)
-	1	-	not specified (1)
-	-	-	Cystic fibrosis;C0149521:Chronic pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Benign	0.030
GPN-Star LLR	N/A	-7.3
GPN-Star score	N/A	7.3
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	0.45	D
Mutation Taster	N/A	3/97	disease causing (ClinVar)
MutationAssessor	Benign	1.3	L
PhyloP100	Uncertain	4.0
popEVE	Benign	-2.9
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.46	N
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Varity_R	N/A	0.24
VESM-3B	Benign	-9.8

Showing 28 of 28 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: rs1800110;

hg19: chr7-117243828;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar