7-117602811-C-G

Position:

• chr7-117602811-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• Conservation: PhyloP100: -0.425

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]

ACMG classification

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, Uncertain_significance=3, Benign=6}. 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	UniProt
CFTR	NM_000492.4	c.2620-15C>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000003084.11

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152176 Hom.: 4 Cov.: 33

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.: 8 AF XY: 0.00296 AC XY: 402 AN XY: 135908

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.: 23 Cov.: 30 AF XY: 0.00206 AC XY: 1494 AN XY: 726818

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.: 3 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74456

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.: 2

Bravo AF: 0.00240

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:2 Benign: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

Other links and lift over

dbSNP: rs139379077; hg19: chr7-117242865;