6-31967002-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_006929.5(SKIC2):c.2341-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000682 in 1,612,816 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 Likely pathogenic (★★).
Frequency
Consequence
NM_006929.5 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SKIC2 | NM_006929.5 | c.2341-2A>G | splice_acceptor_variant, intron_variant | Intron 19 of 27 | ENST00000375394.7 | NP_008860.4 | ||
SKIC2 | XM_011514815.4 | c.2341-2A>G | splice_acceptor_variant, intron_variant | Intron 19 of 24 | XP_011513117.1 | |||
SKIC2 | XM_047419259.1 | c.2341-2A>G | splice_acceptor_variant, intron_variant | Intron 19 of 24 | XP_047275215.1 | |||
SKIC2 | XM_047419260.1 | c.2341-2A>G | splice_acceptor_variant, intron_variant | Intron 19 of 23 | XP_047275216.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 247160Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134526
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460732Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 726682
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74314
ClinVar
Submissions by phenotype
Trichohepatoenteric syndrome 2 Pathogenic:1
This splice site variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory in trans with another pathogenic variant in a 7-month-old female with IUGR, mild hypotonia, mild alopecia, reduced subcutaneous fat, short stature, failure to thrive, renal tubular acidosis, hypocalcemia, hypomagnesemia -
not provided Pathogenic:1
This sequence change affects an acceptor splice site in intron 19 of the SKIV2L gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SKIV2L are known to be pathogenic (PMID: 22444670). This variant is present in population databases (rs781763471, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with trichohepatoenteric syndrome (PMID: 29527791). ClinVar contains an entry for this variant (Variation ID: 561107). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at