CFTR p.Gly542Arg

Variant names:

• chr7-117587778-G-A
• rs113993959
• NM_000492.4:c.1624G>A
• CFTR p.Gly542Arg

Your query was ambiguous. Multiple possible variants found:

• chr7-117587778-G-A
• chr7-117587778-G-C
• chr7-117587778-GGA-AGG
• chr7-117587778-GGA-CGC
• chr7-117587778-GGA-CGG
• chr7-117587778-GGA-CGT

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACMG Germline Pathogenicity v2019). PM1PM2PP3_Moderate

The NM_000492.4(CFTR):c.1624G>A (p.Gly542Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000206 (AC=3) in the gnomAD database across 1,459,832 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000924. 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 (★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.G542E: Uncertain_significance (ClinVar VariationId 2562518, 2 stars); p.G542= (synonymous): Likely_benign (ClinVar VariationId 1577196, 1 star)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• Publications: 792 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 6 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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: 7 pathogenic, 0 benign (OR vs. background: 75.0).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000924 — very rare for AD+AR gene (base 0.0001, raised to 0.0005 by highest known P/LP ClinVar AF 0.0119) — PM2 moderate.
	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.1624G>A p.Gly542Arg	missense	Exon 12 of 27	Prot: NP_000483.3

CFTR NM_000492.4

MANE Select

HGVSc / HGVSpc.1624G>Ap.Gly542Arg

Exon rankExon 12 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.1624G>A p.Gly542Arg	missense	Exon 12 of 27	Prot: ENSP00000003084.6 UniProt:
	CFTR ENST00000699602.1		c.1624G>A p.Gly542Arg	missense	Exon 12 of 27	Prot: ENSP00000514471.1 UniProt:
	CFTR ENST00000889206.1		c.1624G>A p.Gly542Arg	missense	Exon 12 of 26	Prot: ENSP00000559265.1 UniProt:

CFTR ENST00000003084.11

TSL:1MANE Select

HGVSc / HGVSpc.1624G>Ap.Gly542Arg

Exon rankExon 12 of 27

missense

Prot: ENSP00000003084.6UniProt: P13569-1

CFTR ENST00000699602.1

HGVSc / HGVSpc.1624G>Ap.Gly542Arg

Exon rankExon 12 of 27

missense

Prot: ENSP00000514471.1UniProt: A0A8V8TNH2

CFTR ENST00000889206.1

HGVSc / HGVSpc.1624G>Ap.Gly542Arg

Exon rankExon 12 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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000797	AC:2	Hom:	AN:250908	Cov:
GnomAD4 exome	AF: 0.00000206	AC:3	Hom:0	AN:1459832	Cov:28
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 4 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000771	1	12962	0.00	0	23262

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	26
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.96	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.87	D
FuncVEP CTI	Benign	0.39
GPN-Star LLR	N/A	-7.5
GPN-Star score	N/A	7.5
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	1.0	D
Mutation Taster	N/A	40/60	disease causing
MutationAssessor	Uncertain	2.7	M
PhyloP100	Uncertain	4.5
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.088	T
Varity_R	N/A	0.91
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.040
SpliceAI score (max)	Benign	0.16	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;

COSMIC: COSV50045121;

COSMIC: COSV50045121;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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