chr7-117592412-C-T

Position:

• chr7-117592412-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000492.4(CFTR):​c.2245C>T​(p.Leu749Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000743 in 1,613,358 control chromosomes in the GnomAD database, including 1 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 0.00057 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 2.63

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 7-117592412-C-T is Benign according to our data. Variant chr7-117592412-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256251.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=3, Benign=1}. Variant chr7-117592412-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.63 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2245C>T	p.Leu749Leu	synonymous_variant	14/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2245C>T	p.Leu749Leu	synonymous_variant	14/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000611 AC: 153 AN: 250314 Hom.: 0 AF XY: 0.000643 AC XY: 87 AN XY: 135324

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000465

Gnomad ASJ exome AF: 0.000301

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000658

GnomAD4 exome AF: 0.000760 AC: 1111 AN: 1461050 Hom.: 1 Cov.: 32 AF XY: 0.000776 AC XY: 564 AN XY: 726814

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.000422

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000930

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000571 AC: 87 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000470 AC XY: 35 AN XY: 74472

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000852 Hom.: 0

Bravo AF: 0.000529

EpiCase AF: 0.00175

EpiControl AF: 0.00125

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:13

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CFTR: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 20, 2016	Variant summary: The variant affects a conserved nucleotide and results in a synonymous mutation. 5/5 in silico tools predict the variant not to have an impact on splicing while mutation taster predicts the variant to be disease causing. It was predominantly observed in the Non-Finnish European subcohort of the ExAC project at an allele frequency of 0.096% which does not exceed the maximal expected allele frequency of a disease causing CFTR allele (1.3%). It has been reported in patients with wide spectrum of CFTR-related disorders (CF, CBAVD, asthma and COPD) as well as in healthy population and often reported as polymorphism. In one CBAVD patient, this variant was found in cis with R764X (Pallares-Ruiz_1999). In addition, according to Bombieri, it does not lead to exon skipping, suggesting it is indeed not pathogenic. Considering all evidence, the variant was classified as Likely Benign. -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 14, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 30, 2023	In the published literature, the variant has been reported in individuals with cystic fibrosis (CF) (PMIDs: 24782259 (2021) and 7689013 (1993)), emphysema (PMID: 9921909 (1998)), and congenital bilateral absence of the vas deferens (CBAVD) and oligoasthenoteratozoospermia (OAT) (PMID: 10601093 (1999)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CFTR mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant. -

Cystic fibrosis Benign:5

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 11, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 30, 2015	This alteration is classified as likely 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Feb 28, 2020	- -

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Obstructive azoospermia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Reproductive Genetics, University of Münster

Dec 21, 2021

- -

Hereditary pancreatitis Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Jan 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.1
DANN	Benign	0.44

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: rs151235408; hg19: chr7-117232466;