7-117548629-T-TG
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_000492.4(CFTR):c.1210-12_1210-11insG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00143 in 133,216 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000492.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1210-12_1210-11insG | intron_variant | Intron 9 of 26 | ENST00000003084.11 | NP_000483.3 | ||
CFTR-AS1 | NR_149084.1 | n.222-6091_222-6090insC | intron_variant | Intron 2 of 2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00143 AC: 190AN: 133130Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.000393 AC: 83AN: 211464Hom.: 0 AF XY: 0.000365 AC XY: 42AN XY: 114970
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00108 AC: 1463AN: 1357602Hom.: 1 Cov.: 37 AF XY: 0.00108 AC XY: 731AN XY: 676144
GnomAD4 genome AF: 0.00143 AC: 190AN: 133216Hom.: 2 Cov.: 32 AF XY: 0.00156 AC XY: 101AN XY: 64656
ClinVar
Submissions by phenotype
not specified Uncertain:3
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CFTR-related disorder Uncertain:1
The CFTR c.1210-12_1210-11insG variant is predicted to result in an in-frame amino acid insertion (Intronic). Analysis of CFTR poly T and TG tracts indicates that this individual has a 6T/12TG allele (c.1210-34TG[12]T[6]) and a 7T/12TG allele. In the CFTR gene, poly T and TG tract alleles (5T/7T/9T and 10TG/11TG/12TG) are common polymorphic variants. Shorter poly T tracts (such as 5T) combined with longer adjacent poly TG tracts in cis (such as 12TG or 13TG) are known to decrease the efficiency of intron 8 splicing (Cuppens et al. 1998. PubMed ID: 9435322), leading to increased levels of transcripts missing exon 9 which leads to a protein with no chloride channel activity (Delaney et al. 1993. PubMed ID: 7691356; Strong et al. 1993. PubMed ID: 7684641). A poly T tract length of 6 adjacent to TG tract lengths of 11 or 12 (i.e. 6T/11TG and 6T/12TG alleles) have been documented at allele frequencies of up to ~1.5% in Asian populations (Huang et al. 2008. PubMed ID: 18350634; Jin et al. 2012. PubMed ID: 23092102) and have been reported in patients affected with CFTR-related conditions including bronchiectasis, asthma, and chronic bronchitis (Lee et al. 2003. PubMed ID: 12952861; Wang et al. 2012. PubMed ID: 23554779; Dahl et al. 2005. PubMed ID: 16212675; Kim et al. 2010. PubMed ID: 20879059). However, 6T/11TG and 6T/12TG alleles have also been documented in healthy controls (Fujiki et al. 2004. PubMed ID: 15121783; Wang et al. 2012. PubMed ID: 23554779; Chang et al. 2007. PubMed ID: 17539902; Kim et al. 2010. PubMed ID: 20879059). A 6T/13TG allele has been documented in trans with a pathogenic variant in patients with congenital bilateral absence of the vas deferens (Dayangaç et al. 2004. PubMed ID: 15070876; Viel et al. 2005. PubMed ID: 15562283). At this time, the clinical significance of the CFTR 6T/12TG allele identified in this patient is uncertain due to the absence of conclusive functional and genetic evidence. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at