7-117592027-T-G

Position:

• chr7-117592027-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000492.4(CFTR):​c.1860T>G​(p.His620Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 2.37

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_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.962
• PP5: Variant 7-117592027-T-G is Pathogenic according to our data. Variant chr7-117592027-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53407.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, not_provided=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.1860T>G	p.His620Gln	missense_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.1860T>G	p.His620Gln	missense_variant	14/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Uncertain:1 Other:1

Pathogenic, 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: PS3_MOD, PM3, PM2_SUP, PM5_STR, PP3, PP4 -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 10, 2014	The p.H620Q (also known as c.1860T>G) variant is located in exon 14 of the CFTR gene. This variant results from an T to G substitution at nucleotide position 1860. The histidine at codon 620 is replaced by glutamine, an amino acid with similar properties. This variant has been described in one individual with pancreatic insufficiency, recurrent pulmonary infections, and elevated sweat chloride, who was reported to be compound heterozygous for deltaF508 (Vankeerberghen et al. Hum. Mol. Genet. 1998 Oct;7(11):1761-9). Multiple in vitro studies have shown this variant, which is located in the regulatory domain of CFTR, results in a normally processed protein and increases chloride channel activity above that of the wild type protein (Vankeerberghen et al. Hum. Mol. Genet. 1998 Oct;7(11):1761-9l; Choi et al. Nature 2001 Mar;410(6824):94-7; Wei L et al. FEBS Lett. 1998 Nov 13;439(1-2):121-6). This variant has been detected in trans with a pathogenic mutation in CFTR in a set of twins by our laboratory. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. This amino acid position is highly conserved on sequence alignment of available vertebrate species. This variant is predicted to be probably damaging by PolyPhen and tolerated by SIFT in silico analyses. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 26, 2020	This variant has not been reported in the literature in individuals with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 53407). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects CFTR protein function (PMID: 9736778, 9849891, 22722932, 11242048). This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 620 of the CFTR protein (p.His620Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	T;.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.92	D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.96	D;D;D;D
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.075	N;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.6	D;.;D;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.017	D;.;D;.
Sift4G	Uncertain	0.011	D;.;D;.
Polyphen		1.0	D;.;.;.
Vest4		0.93
MutPred		0.86		Gain of catalytic residue at H620 (P = 0.0721);.;.;.;
MVP		0.97
MPC		0.0040
ClinPred		0.95	D
GERP RS		4.3
Varity_R		0.82
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.73		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.73		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397508315; hg19: chr7-117232081;