7-117611646-G-A

Variant names:

• chr7-117611646-G-A
• rs200321110
• NM_000492.4:c.3205G>A
• CFTR p.Gly1069Arg

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+11 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 11 classification points (ACMG Germline Pathogenicity v2019). PS1PS3PM1PP5

The NM_000492.4(CFTR):c.3205G>A (p.Gly1069Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000136 (AC=220) in the gnomAD database across 1,613,472 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00087. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (no review stars). ClinVar reports functional evidence for this variant: "SCV001180539: Functional studies demonstrated that while the p.G1069R variant in CFTR does not impact protein maturation or conductance, it does reduce the probability of channel opening (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45)." and additional evidence is available in ClinVar. This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:16 U:9
• 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 11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, 1-star ClinVar pathogenic — strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 1 star).
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV001180539: Functional studies demonstrated that while the p.G1069R variant in CFTR does not impact protein maturation or conductance, it does reduce the probability of channel opening (Seibert FS et al. J. Biol. Chem., 1996 Jun;271:15139-45).; SCV005906064: "Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product." PMID:8662892; SCV000601092: Experimental studies indicate this variant induces an ion channel gating defect in the CFTR protein (PMIDs: 8662892 (1996), 22210114 (2012)).; SCV005418403: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000603016: "In vitro functional analyses demonstrate that this variant does not alter protein expression, but reduces channel function (Seibert 1996)." PMID: 8662892
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 16 pathogenic, 0 benign (OR vs. background: 165.0).
	PP5Reputable source reports pathogenic		ClinVar 0-star pathogenic — supporting (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 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.3205G>A	p.Gly1069Arg	missense	Exon 20 of 27	NP_000483.3
	CFTR-AS2	NR_199597.1		n.177+4583C>T		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>A	p.Gly1069Arg	missense	Exon 20 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.3205G>A	p.Gly1069Arg	missense	Exon 20 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.3118G>A	p.Gly1040Arg	missense	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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000243	AC:37	Hom:0	AN:151976	Cov:31
GnomAD2 exomes	AF: 0.000255	AC:64	Hom:	AN:250934	Cov:
GnomAD4 exome	AF: 0.000125	AC:183	Hom:0	AN:1461378	Cov:31
GnomAD4 genome	AF: 0.000243	AC:37	Hom:0	AN:152094	Cov:31
TOPMed (Bravo)	AF: 0.000264	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000190	AC:60	Hom:0	AN:316230	Cov:
Local & regional cohorts 7 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: 0.000936	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000538	AC:7	Hom:	AN:13006	Cov:
Korea4K (4,157 Koreans)	AF: 0.000138	AC:1	Hom:	AN:7224	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122174	Cov:
Turkish Variome	AF: 0.000744	AC:5	Hom:0	AN:6718	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.00134	AC:12	Hom:0	AN:8960	Cov:

Showing 13 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000104 *	1	9614	0.00 *	0	10412
BipEx(Bipolar disorder (including schizoaffective))	0.000176	5	28414	0.000139	4	28844
Epi25(Epilepsy)	0.000453	19	41956	0.000254	17	66876
SCHEMA(Schizophrenia)	0.000283	32	113184	0.000215	41	190670

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
6	3	-	Cystic fibrosis (9)
3	2	-	CFTR-related disorder (5)
2	2	-	not provided (4)
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	-	Hereditary pancreatitis (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	24
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Benign	0.89
DEOGEN2	Uncertain	0.50	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-7.4
GPN-Star score	N/A	7.2
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.24	T
MetaSVM	Uncertain	-0.0072	T
Mutation Taster	N/A	11/89	disease causing (ClinVar)
MutationAssessor	Benign	1.3	L
PhyloP100	Uncertain	6.9
popEVE	Benign	-3.0
PrimateAI	Pathogenic	0.85	D
PromoterAI	N/A	-0.0040	Neutral
PROVEAN	Benign	0.14	N
REVEL	Uncertain	0.60
Sift	Benign	0.48	T
Sift4G	Benign	0.094	T
Varity_R	N/A	0.57
VESM-3B	Benign	-7.6

Showing 28 of 28 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;

COSMIC: COSV50043830;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar