rs139379077

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000492.4(CFTR):c.2620-15C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,194 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 23 hom. )

Consequence

CFTR
NM_000492.4 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:12

Conservation

PhyloP100: -0.425

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 7-117602811-C-G is Benign according to our data. Variant chr7-117602811-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35844.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=6, Uncertain_significance=3}. Variant chr7-117602811-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00189 (2767/1460900) while in subpopulation MID AF= 0.0331 (191/5766). AF 95% confidence interval is 0.0293. There are 23 homozygotes in gnomad4_exome. There are 1494 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2620-15C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2620-15C>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00218

AC:

332

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00484

Gnomad ASJ

AF:

0.0248

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.00717

GnomAD3 exomes

AF:

0.00272

AC:

685

AN:

251464

Hom.:

AF XY:

0.00296

AC XY:

402

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.00309

Gnomad ASJ exome

AF:

0.0198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00251

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00189

AC:

2767

AN:

1460900

Hom.:

Cov.:

AF XY:

0.00206

AC XY:

1494

AN XY:

726818

show subpopulations

Gnomad4 AFR exome

AF:

0.000927

Gnomad4 AMR exome

AF:

0.00297

Gnomad4 ASJ exome

AF:

0.0217

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00155

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00130

Gnomad4 OTH exome

AF:

0.00437

GnomAD4 genome

AF:

0.00217

AC:

330

AN:

152294

Hom.:

Cov.:

AF XY:

0.00239

AC XY:

178

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000216

Gnomad4 AMR

AF:

0.00484

Gnomad4 ASJ

AF:

0.0248

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00197

Gnomad4 OTH

AF:

0.00710

Alfa

AF:

0.00504

Hom.:

Bravo

AF:

0.00240

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:2Benign:5

Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	May 25, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 26, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM3, PP4, BS2 -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 19, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CFTR: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 14, 2019	This variant is associated with the following publications: (PMID: 19017867, 20100616, 16251901, 16128988, 27264265, 9521595, 24272871, 9272157, 29174009, 25900089, 29807875, 28408918, 26500004, 28040058, 28546993, 27884173, 10875853, 15070876) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 19, 2023	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

CFTR-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary pancreatitis

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.062

DANN

Benign

0.51

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over