7-117590439-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000492.4(CFTR):c.1766G>C(p.Ser589Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000276 in 1,448,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S589N) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CFTR NM_000492.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 5.68

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 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117590439-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 53384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1766G>C	p.Ser589Thr	missense_variant, splice_region_variant	13/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1766G>C	p.Ser589Thr	missense_variant, splice_region_variant	13/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000276 AC: 4 AN: 1448114 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 720218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000769

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 05, 2023

Variant summary: CFTR c.1766G>C (p.Ser589Thr) results in a conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This variant falls onto the last nucleotide of exon 13, therefore can also affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249234 control chromosomes (gnomAD v2.1 exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1766G>C has been reported in the literature in a compound heterozygous individuals affected with Cystic Fibrosis, who carried a pathogenic 2nd variant (Kinnunen_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. However, another variant affecting the same nucleotide (CFTR c.1766G>A (p.Ser589Asn)) is classified as pathogenic by our lab. The following publication have been ascertained in the context of this evaluation (PMID: 16051530). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Cystic fibrosis Other:1

not provided, no classification provided

literature only

ClinVar Staff, National Center for Biotechnology Information (NCBI)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
Cadd	Uncertain	25
Dann	Uncertain	0.97
DEOGEN2	Uncertain	0.43	T;.;T;.
Eigen	Benign	-0.10
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	0.085	N;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.2	N;.;N;.
REVEL	Uncertain	0.55
Sift	Benign	0.069	T;.;D;.
Sift4G	Uncertain	0.052	T;.;D;.
Polyphen		0.066	B;.;.;.
Vest4		0.63
MutPred		0.83		Gain of ubiquitination at K584 (P = 0.1162);.;.;.;
MVP		0.99
MPC		0.0042
ClinPred		0.76	D
GERP RS		4.8
Varity_R		0.67
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.83		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.83		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508300; hg19: chr7-117230493;