rs371315682

Positions:

chr7-117602820-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000492.4(CFTR):c.2620-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000297 in 1,613,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

CFTR
NM_000492.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0007007

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:8

Conservation

PhyloP100: 1.62

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 Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.5).

BP6

Variant 7-117602820-T-C is Benign according to our data. Variant chr7-117602820-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53530.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=4, Benign=2}. Variant chr7-117602820-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2620-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2620-6T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000492.4	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000361

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000541

AC:

136

AN:

251476

Hom.:

AF XY:

0.000589

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00402

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000290

AC:

424

AN:

1461406

Hom.:

Cov.:

AF XY:

0.000271

AC XY:

197

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00346

Gnomad4 NFE exome

AF:

0.000206

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000361

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000484

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000268

Hom.:

Bravo

AF:

0.000136

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:1Benign:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 04, 2024	The c.2620-6T>C intronic variant results (also known as 2752-6T>C) from a T to C substitution 6 nucleotides upstream from coding exon 16 in the CFTR gene. This variant was identified in a cohort of Hispanic individuals with clinical symptoms of cystic fibrosis; however, complete genotype and phenotype information was not provided (Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In addition, this variant was identified in a healthy adult African American female in trans with p.F508del (Wallerstein VI et al. Case Rep Genet, 2017 Jan;2017:7281023). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Based on available evidence to date, the clinical significance of this alteration remains unclear. -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 11, 2021	the variant does not result in CFTR-RD neither -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	- -

not provided

Uncertain:2Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 09, 2016	- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 22, 2021

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 23, 2022

Variant summary: CFTR c.2620-6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. These predictions are corroborated by experimental evidence in a minigene assay, in which the variant was reported to have no impact on splicing (e.g. Leman_2018). The variant allele was found at a frequency of 0.00054 in 251668 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00054 vs 0.0063), allowing no conclusion about variant significance. c.2620-6T>C has been reported in the literature in individuals screened for CFTR mutations (e.g. Zhou_2013, Schrijver_2005, Lefterova_2016) without evidence for disease causality, including a report of the variant being found in trans with the common pathogenic p.F508Del mutation in a healthy pregnant woman, suggesting that c.2620-6T>C may be benign or a very mild disease allele (e.g.Wallerstein_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign/likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign. -

CFTR-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Benign

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00070

dbscSNV1_RF

Benign

0.088

SpliceAI score (max)

0.010

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