7-117592169-C-T

Variant names:

• chr7-117592169-C-T
• rs1800100
• NM_000492.4:c.2002C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000492.4(CFTR):​c.2002C>T​(p.Arg668Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,613,866 control chromosomes in the GnomAD database, including 60 homozygotes. 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. R668S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0060 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0085 (57 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:19 B:7 O:1
• Conservation: PhyloP100: 1.52
• Publications: 74 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, 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)

ACMG classification

Our verdict: Likely_benign. The variant received -3 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.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.2002C>T	p.Arg668Cys	missense	Exon 14 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.2002C>T	p.Arg668Cys	missense	Exon 14 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.2002C>T	p.Arg668Cys	missense	Exon 14 of 27	ENSP00000514471.1
	CFTR	ENST00000889206.1		c.1915C>T	p.Arg639Cys	missense	Exon 13 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 921 AN: 152166 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00594

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00891

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00600 AC: 1501 AN: 250108 AF XY: 0.00608

Gnomad AFR exome AF: 0.00211

Gnomad AMR exome AF: 0.00622

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00554

Gnomad NFE exome AF: 0.00957

Gnomad OTH exome AF: 0.00688

GnomAD4 exome AF: 0.00845 AC: 12351 AN: 1461582 Hom.: 57 Cov.: 32 AF XY: 0.00798 AC XY: 5803 AN XY: 727080

African (AFR) AF: 0.00158 AC: 53 AN: 33476

American (AMR) AF: 0.00599 AC: 268 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000255 AC: 22 AN: 86248

European-Finnish (FIN) AF: 0.00633 AC: 337 AN: 53202

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5768

European-Non Finnish (NFE) AF: 0.0101 AC: 11201 AN: 1111942

Other (OTH) AF: 0.00750 AC: 453 AN: 60392

GnomAD4 genome AF: 0.00605 AC: 921 AN: 152284 Hom.: 3 Cov.: 32 AF XY: 0.00586 AC XY: 436 AN XY: 74464

African (AFR) AF: 0.00219 AC: 91 AN: 41560

American (AMR) AF: 0.00882 AC: 135 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00594 AC: 63 AN: 10614

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00891 AC: 606 AN: 68016

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.00796 Hom.: 24

Bravo AF: 0.00593

TwinsUK AF: 0.0119 AC: 44

ALSPAC AF: 0.0112 AC: 43

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00610 AC: 741

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00877

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	5	Cystic fibrosis (9)
1	7	-	not provided (9)
1	3	-	CFTR-related disorder (4)
-	1	1	Hereditary pancreatitis (2)
-	1	1	not specified (2)
-	1	-	Chronic sinusitis (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	-	Lung disease, non-specific (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0084	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.94
MVP		1.0
MPC		0.014
ClinPred		0.039	T
GERP RS		4.5
Varity_R		0.73
gMVP		0.79
Mutation Taster		=56/44	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 13

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

Other links and lift over

dbSNP: rs1800100; hg19: chr7-117232223;