7-117534295-G-A

Variant names:

• chr7-117534295-G-A
• rs1800079
• NM_000492.4:c.509G>A
• CFTR p.Arg170His

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPP3_Moderate

The NM_000492.4(CFTR):c.509G>A (p.Arg170His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.000514 (AC=819) in the gnomAD database across 1,593,672 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000431. 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: "SCV001477556: Functional analyses of the variant show a slight increase in exon 5 skipping (Aissat 2013), but mature protein expression levels and chloride transport activity similar to wildtype (LaRusch 2014). However, the variant protein exhibits impaired bicarbonate transport, which is also observed for other CFTR variants enriched in pancreatitis patients (LaRusch 2014). PMID:25033378". Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R170C: Uncertain_significance (ClinVar VariationId 455782, 2 stars); p.R170= (synonymous): Likely_benign (ClinVar VariationId 695287, 2 stars); p.R170S: Uncertain_significance (ClinVar VariationId 1053721, 2 stars) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:18 B:3
• Conservation: PhyloP100: 7.14
• Publications: 35 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: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV001477556: Functional analyses of the variant show a slight increase in exon 5 skipping (Aissat 2013), but mature protein expression levels and chloride transport activity similar to wildtype (LaRusch 2014). However, the variant protein exhibits impaired bicarbonate transport, which is also observed for other CFTR variants enriched in pancreatitis patients (LaRusch 2014). PMID: 25033378
	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: 9 pathogenic, 0 benign (OR vs. background: 95.0).
	PM2Absent/extremely low in population databases		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.000431 — borderline rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.0119) — PM2 supporting.
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (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.509G>A p.Arg170His	missense	Exon 5 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.509G>Ap.Arg170His

Exon rankExon 5 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.509G>A p.Arg170His	missense	Exon 5 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.509G>A p.Arg170His	missense	Exon 5 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.509G>A p.Arg170His	missense	Exon 5 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.509G>Ap.Arg170His

Exon rankExon 5 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.509G>Ap.Arg170His

Exon rankExon 5 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.509G>Ap.Arg170His

Exon rankExon 5 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: 0.000434	AC:66	Hom:0	AN:152002	Cov:33
GnomAD2 exomes	AF: 0.000499	AC:125	Hom:	AN:250408	Cov:
GnomAD4 exome	AF: 0.000522	AC:752	Hom:0	AN:1441552	Cov:26
GnomAD4 genome	AF: 0.000440	AC:67	Hom:0	AN:152120	Cov:33
TOPMed (Bravo)	AF: 0.000502	AC:133	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000506	AC:268	Hom:0	AN:529980	Cov:
Local & regional cohorts 6 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.000246	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000615	AC:8	Hom:	AN:13002	Cov:
GenomeAsia100K	AF: 0.000289	AC:1	Hom:	AN:3478	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000160	AC:2	Hom:0	AN:122488	Cov:
Turkish Variome	AF: 0.000605	AC:4	Hom:0	AN:6610	Cov:
UK10K	AF: 0.000264	AC:2	Hom:	AN:7562	Cov:

Showing 12 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000422 *	4	9484	0.000388 *	4	10308
BipEx(Bipolar disorder (including schizoaffective))	0.000388	11	28384	0.000208	6	28794
Epi25(Epilepsy)	0.000406	17	41884	0.000643	43	66834
SCHEMA(Schizophrenia)	0.000485	59	121634	0.000462	88	190460

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
-	8	3	Cystic fibrosis (11)
-	5	-	not provided (5)
2	2	-	CFTR-related disorder (4)
1	-	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	1	-	Chronic pancreatitis (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 (1)
-	1	-	Hereditary pancreatitis (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	23
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
GPN-Star LLR	N/A	-7.4
GPN-Star score	N/A	7.4
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	0.70	D
Mutation Taster	N/A	6/94	disease causing (ClinVar)
MutationAssessor	Benign	1.9	L
PhyloP100	Uncertain	7.1
popEVE	Benign	-3.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0010	D
Varity_R	N/A	0.44
VESM-3B	Benign	-5.8

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.030
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2
Splicevardb	N/A	2.0

Showing 3 of 3 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: rs1800079;

hg19: chr7-117174349;

COSMIC: COSV104520322;

COSMIC: COSV104520322;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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