chr7-117587778-G-T

Variant names:

• chr7-117587778-G-T
• rs113993959
• NM_000492.4:c.1624G>T
• CFTR p.Gly542*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 20 classification points (ACMG Germline Pathogenicity v2019). PVS1PS3PP5_Very_Strong

The NM_000492.4(CFTR):c.1624G>T (p.Gly542*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.000363 (AC=585) in the gnomAD database across 1,612,120 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000503. In-silico predictor (BayesDel (noAF)) 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 Pathogenic/Likely Pathogenic (★★★★). ClinVar reports functional evidence for this variant: "SCV000889294: A functional study has shown that this variant abrogates CFTR chloride channel activity (PMID:7522901 (1993)).".

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Pathogenic practice guideline P:41 O:3
• Conservation: PhyloP100: 4.51
• Publications: 15 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: Pathogenic. The variant received 20 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 12 of 27) at amino acid 542 of 1480, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV000889294: A functional study has shown that this variant abrogates CFTR chloride channel activity (PMID: 7522901 (1993)).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 4 star(s). ClinVar submissions strongly and reliably favor pathogenicity (41/41 total P/LP).

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.1624G>T p.Gly542*	stop_gained	Exon 12 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.1624G>Tp.Gly542*

Exon rankExon 12 of 27

stop_gained

Prot: NP_000483.3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	CFTR ENST00000003084.11	TSL:1MANE Select	c.1624G>T p.Gly542*	stop_gained	Exon 12 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.1624G>T p.Gly542*	stop_gained	Exon 12 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.1624G>T p.Gly542*	stop_gained	Exon 12 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.1624G>Tp.Gly542*

Exon rankExon 12 of 27

stop_gained

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.1624G>Tp.Gly542*

Exon rankExon 12 of 27

stop_gained

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.1624G>Tp.Gly542*

Exon rankExon 12 of 26

stop_gained

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: 0.000296	AC:45	Hom:0	AN:152178	Cov:32
GnomAD2 exomes	AF: 0.000339	AC:85	Hom:	AN:250908	Cov:
GnomAD4 exome	AF: 0.000370	AC:540	Hom:0	AN:1459824	Cov:28
GnomAD4 genome	AF: 0.000295	AC:45	Hom:0	AN:152296	Cov:32
TOPMed (Bravo)	AF: 0.000393	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000406	AC:190	Hom:0	AN:467986	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2342	Cov:
ESP6500 (Exome Variant Server)	AF: 0.00138	AC:18	Hom:	AN:13006	Cov:
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5170	Cov:
UK10K	AF: 0.000397	AC:3	Hom:	AN:7562	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9622	0.00 *	0	10428
BipEx(Bipolar disorder (including schizoaffective))	0.000106	3	28418	0.000312	9	28844
Epi25(Epilepsy)	0.000262	11	41948	0.000419	28	66842
SCHEMA(Schizophrenia)	0.000254	31	121904	0.000351	67	190702

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

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: practice guideline

Pathogenic	VUS	Benign	Condition
21	-	-	Cystic fibrosis (22)
11	-	-	not provided (12)
3	-	-	CFTR-related disorder (3)
2	-	-	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)
2	-	-	Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation (2)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
1	-	-	Cystic fibrosis diagnostic test (1)
-	-	-	Hereditary pancreatitis (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	39
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Uncertain	0.90	D
GPN-Star LLR	N/A	-11
GPN-Star score	N/A	11
Mutation Taster	N/A	0/200	disease causing (ClinVar)
PhyloP100	Uncertain	4.5

Showing 12 of 12 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.090
SpliceAI score (max)	Benign	0.13	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: rs113993959;

hg19: chr7-117227832;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar