7-117611646-G-T

Variant names:

• chr7-117611646-G-T
• rs200321110
• NM_000492.4:c.3205G>T
• CFTR p.Gly1069*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2

The NM_000492.4(CFTR):c.3205G>T (p.Gly1069*) 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 0.00000658 (AC=1) in the gnomAD database across 151,976 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000147. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. 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.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: CFTR NM_000492.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.85
• Publications: 52 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)

ENSG00000083622 (HGNC:40145):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 10 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 20 of 27) at amino acid 1069 of 1480, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000147 — very rare for AD+AR gene (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.3205G>T	p.Gly1069*	stop_gained	Exon 20 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4583C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.3205G>T	p.Gly1069*	stop_gained	Exon 20 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3205G>T	p.Gly1069*	stop_gained	Exon 20 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3118G>T	p.Gly1040*	stop_gained	Exon 19 of 26	ENSP00000559265.1	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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000658	AC:1	Hom:0	AN:151976	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF: 0.00000658	AC:1	Hom:0	AN:151976	Cov:31
TOPMed (Bravo)	AF: 0.00000378	AC:1	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:316230	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	38
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
GPN-Star LLR	N/A	-9.8
GPN-Star score	N/A	9.8
Mutation Taster	N/A	0/200	disease causing (fs/PTC)
PhyloP100	Uncertain	6.9
PromoterAI	N/A	0.010	Neutral

Showing 13 of 13 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	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.

Other links and lift over

dbSNP: rs200321110;

hg19: chr7-117251700;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar