rs75789129

chr7-117587820-A-G

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_000492.4(CFTR):c.1666A>G(p.Ile556Val) variant causes a missense change. The variant allele was found at a frequency of 0.00127 in 1,598,980 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I556L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (35 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:11
• Conservation: PhyloP100: 3.90

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 -11 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000492.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.007845759).
• BP6: Variant 7-117587820-A-G is Benign according to our data. Variant chr7-117587820-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 7196.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=4, Likely_benign=5, Pathogenic=1}. Variant chr7-117587820-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00175 (267/152310) while in subpopulation EAS AF= 0.0499 (259/5186). AF 95% confidence interval is 0.0449. There are 6 homozygotes in gnomad4. There are 137 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1666A>G	p.Ile556Val	missense_variant	12/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1666A>G	p.Ile556Val	missense_variant	12/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.00175 AC: 266 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0496

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00351 AC: 881 AN: 250736 Hom.: 26 AF XY: 0.00317 AC XY: 430 AN XY: 135494

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0472

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00122 AC: 1759 AN: 1446670 Hom.: 35 Cov.: 26 AF XY: 0.00115 AC XY: 828 AN XY: 720812

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0409

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000910

Gnomad4 OTH exome AF: 0.00202

GnomAD4 genome AF: 0.00175 AC: 267 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00184 AC XY: 137 AN XY: 74476

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0499

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00177 Hom.: 4

Bravo AF: 0.00213

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.0100 AC: 36 AN: 3476

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:2 Benign:6

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Sep 07, 2021	- -
Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 08, 2022	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	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2017	- -
Uncertain significance, flagged submission	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, BS1, BS2 -
Uncertain significance, flagged submission	literature only	OMIM	May 15, 1994	- -

CFTR-related disorder Pathogenic:1 Benign:2

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 24, 2024	- -
Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 23, 2018	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 13, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2023	BS1, BS2 -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 17, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D;.;T;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.066
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.95	D;D;D;D
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	-0.30	N;.;.;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.070	N;.;N;.
REVEL	Uncertain	0.44
Sift	Benign	0.54	T;.;T;.
Sift4G	Benign	0.23	T;.;T;.
Polyphen		0.33	B;.;.;.
Vest4		0.85
MVP		0.97
MPC		0.0048
ClinPred		0.070	T
GERP RS		5.3
Varity_R		0.22
gMVP		0.81

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: rs75789129; hg19: chr7-117227874; COSMIC: COSV105835392; COSMIC: COSV105835392;