rs1060503162
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_000492.4(CFTR):c.372C>T(p.Gly124=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
CFTR
NM_000492.4 synonymous
NM_000492.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.83
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: 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.372C>T | p.Gly124= | synonymous_variant | 4/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.372C>T | p.Gly124= | synonymous_variant | 4/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461370Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727000
GnomAD4 exome
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1
AN:
1461370
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31
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0
AN XY:
727000
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Cystic fibrosis Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2021 | This sequence change affects codon 124 of the CFTR mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CFTR protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with idiopathic chronic pancreatitis (PMID: 25492507). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 10, 2021 | The c.372C>T variant (also known as p.G124G), located in coding exon 4, results from a C to T substitution at nucleotide position 372 of the CFTR gene. This nucleotide substitution does not change the amino acid at codon 124. This variant has been detected in conjunction with pathogenic mutations in CFTR by our laboratory; however, the phase (whether in cis or trans) is not known. In addition, this alteration has been detected in an individual with idiopathic chronic pancreatitis (Nakano E et al. Dig. Dis. Sci., 2015 May;60:1297-307). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 11, 2019 | - - |
CFTR-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 30, 2020 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at