rs143486492

Variant names:

• chr7-117540120-G-A
• rs143486492
• NM_000492.4:c.890G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PP2 BP4_Moderate BP6

The NM_000492.4(CFTR):​c.890G>A​(p.Arg297Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000885 in 1,613,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R297W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:9
• Conservation: PhyloP100: 6.39
• Publications: 26 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):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• 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)

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• BP4: Computational evidence support a benign effect (MetaRNN=0.19872731).
• BP6: Variant 7-117540120-G-A is Benign according to our data. Variant chr7-117540120-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 54082.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.890G>A	p.Arg297Gln	missense	Exon 8 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.890G>A	p.Arg297Gln	missense	Exon 8 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.890G>A	p.Arg297Gln	missense	Exon 8 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.890G>A	p.Arg297Gln	missense	Exon 8 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152058 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000567 AC: 142 AN: 250572 AF XY: 0.000554

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000907 AC: 1325 AN: 1460952 Hom.: 0 Cov.: 30 AF XY: 0.000876 AC XY: 637 AN XY: 726824

African (AFR) AF: 0.000120 AC: 4 AN: 33464

American (AMR) AF: 0.000358 AC: 16 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39682

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53384

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00112 AC: 1243 AN: 1111236

Other (OTH) AF: 0.000795 AC: 48 AN: 60352

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74394

African (AFR) AF: 0.000169 AC: 7 AN: 41514

American (AMR) AF: 0.000196 AC: 3 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00119 AC: 81 AN: 68006

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000910 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	4	Cystic fibrosis (9)
-	5	1	not provided (6)
-	-	3	not specified (3)
-	-	1	CFTR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.4
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.038	D
Polyphen		0.13	B
Vest4		0.83
MVP		0.98
MPC		0.0044
ClinPred		0.037	T
GERP RS		5.4
Varity_R		0.72
gMVP		0.89
Mutation Taster		=8/92	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs143486492; hg19: chr7-117180174; COSMIC: COSV99133519;