NM_000166.6:c.-17G>A
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000166.6(GJB1):c.-17G>A variant causes a splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000166.6 splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GJB1 | NM_000166.6 | c.-17G>A | splice_region_variant | Exon 1 of 2 | ENST00000361726.7 | NP_000157.1 | ||
GJB1 | NM_000166.6 | c.-17G>A | 5_prime_UTR_variant | Exon 1 of 2 | ENST00000361726.7 | NP_000157.1 | ||
GJB1 | NM_001097642.3 | c.-16-357G>A | intron_variant | Intron 1 of 1 | NP_001091111.1 | |||
GJB1 | XM_011530907.3 | c.-16-357G>A | intron_variant | Intron 1 of 1 | XP_011529209.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 22
GnomAD4 exome Cov.: 0
GnomAD4 genome Cov.: 22
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease X-linked dominant 1 Pathogenic:3
Variant summary: GJB1 c.-17G>A (also known as -373G>A) is located in the untranslated mRNA region upstream of the initiation codon. The variant was absent in 21639 control chromosomes. c.-17G>A has been reported in the literature in multiple individuals affected with Charcot-Marie-Tooth disease X-linked dominant 1 (example: Murphy_2011). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 21504505). ClinVar contains an entry for this variant (Variation ID: 246014). Based on the evidence outlined above, the variant was classified as pathogenic. -
The GJB1 c.-17G>A variant occurs in the last base of the 5' untranslated region. This variant has been reported in at least four studies, in which it is found in a total of 26 individuals from eight unrelated families with Charcot-Marie-Tooth neuropathy X type 1 disorder (CMT1X) (Murphy et al. 2011; Arthur-Farraj et al. 2012; Antoniadi et al. 2015; Tomaselli et al. 2017). Affected individuals included both heterozygous females and hemizygous males, and this variant was shown to segregate with disease in five families (Murphy et al. 2011; Tomaselli et al. 2017). The c.-17G>A variant is not found in the Genome Aggregation Database despite good sequence coverage, so the variant is presumed to be rare. Based on the collective evidence and application of the ACMG criteria, the c.-17G>A variant is classified as pathogenic for Charcot-Marie-Tooth neuropathy X type 1. -
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not provided Pathogenic:2
Not found in the gnomAD genomes dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Splicing predictions are inconclusive. Nucleotide conservation is uninformative. Strong co-segregation with disease, and data includes affected and unaffected individuals from multiple families. -
No data available from control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 23011429, 22464564, 28768847, 26392352, 31827005, 21504505, 28283593) -
Charcot-Marie-Tooth Neuropathy X Pathogenic:1
This variant occurs in a non-coding region of the GJB1 gene. It does not change the encoded amino acid sequence of the GJB1 protein. This variant also falls at the last nucleotide of exon 1, which is part of the consensus splice site for this exon. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This variant has been observed in individuals with Charcot-Marie-Tooth disease (PMID: 21504505, 22464564, 26392352, 28283593, 28768847; internal datadatabase). It has also been observed to segregate with disease in related individuals. This variant is also known as c.-373G>A. ClinVar contains an entry for this variant (Variation ID: 246014). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at