rs17140229

Variant names:

• chr7-117590229-T-C
• rs17140229
• NM_000492.4:c.1680-124T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000492.4(CFTR):​c.1680-124T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0215 in 1,126,198 control chromosomes in the GnomAD database, including 3,680 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (2249 hom., cov: 32)
  • Exomes 𝑓: 0.010 (1431 hom.)
• Consequence: CFTR NM_000492.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.462
• Publications: 15 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-117590229-T-C is Benign according to our data. Variant chr7-117590229-T-C is described in ClinVar as Benign. ClinVar VariationId is 1251170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.32 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1680-124T>C		intron_variant	Intron 12 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1680-124T>C		intron_variant	Intron 12 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0934 AC: 14194 AN: 151894 Hom.: 2250 Cov.: 32

Gnomad AFR AF: 0.325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0334

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00118

Gnomad OTH AF: 0.0690

GnomAD4 exome AF: 0.0102 AC: 9961 AN: 974186 Hom.: 1431 AF XY: 0.00896 AC XY: 4371 AN XY: 487668

African (AFR) AF: 0.336 AC: 7986 AN: 23760

American (AMR) AF: 0.0189 AC: 550 AN: 29030

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 34 AN: 18510

East Asian (EAS) AF: 0.00 AC: 0 AN: 34200

South Asian (SAS) AF: 0.000617 AC: 39 AN: 63254

European-Finnish (FIN) AF: 0.0000292 AC: 1 AN: 34276

Middle Eastern (MID) AF: 0.0177 AC: 72 AN: 4058

European-Non Finnish (NFE) AF: 0.000648 AC: 470 AN: 725164

Other (OTH) AF: 0.0193 AC: 809 AN: 41934

GnomAD4 genome AF: 0.0935 AC: 14215 AN: 152012 Hom.: 2249 Cov.: 32 AF XY: 0.0894 AC XY: 6641 AN XY: 74320

African (AFR) AF: 0.325 AC: 13468 AN: 41452

American (AMR) AF: 0.0333 AC: 508 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4814

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00118 AC: 80 AN: 67888

Other (OTH) AF: 0.0683 AC: 144 AN: 2108

Alfa AF: 0.0535 Hom.: 291

Bravo AF: 0.107

Asia WGS AF: 0.0160 AC: 55 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.6
DANN	Benign	0.73
PhyloP100		0.46
Mutation Taster		=100/0	polymorphism (auto)

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: rs17140229; hg19: chr7-117230283;