6-83854160-A-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001400774.1(RIPPLY2-CYB5R4):c.-29A>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000172 in 1,613,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001400774.1 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RIPPLY2 | ENST00000369689.6 | c.238A>T | p.Arg80* | stop_gained, splice_region_variant | Exon 3 of 4 | 1 | NM_001009994.3 | ENSP00000358703.1 | ||
RIPPLY2 | ENST00000369687.2 | c.64A>T | p.Arg22* | stop_gained, splice_region_variant | Exon 2 of 3 | 2 | ENSP00000358701.1 | |||
RIPPLY2 | ENST00000635617.1 | n.571A>T | non_coding_transcript_exon_variant | Exon 1 of 1 | 6 | |||||
ENSG00000287705 | ENST00000656981.1 | n.8T>A | non_coding_transcript_exon_variant | Exon 1 of 1 |
Frequencies
GnomAD3 genomes AF: 0.000223 AC: 34AN: 152228Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251422Hom.: 0 AF XY: 0.000132 AC XY: 18AN XY: 135908
GnomAD4 exome AF: 0.000167 AC: 244AN: 1461472Hom.: 0 Cov.: 31 AF XY: 0.000164 AC XY: 119AN XY: 727048
GnomAD4 genome AF: 0.000223 AC: 34AN: 152228Hom.: 0 Cov.: 33 AF XY: 0.000229 AC XY: 17AN XY: 74376
ClinVar
Submissions by phenotype
not provided Pathogenic:3Uncertain:2
This sequence change creates a premature translational stop signal (p.Arg80*) in the RIPPLY2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the RIPPLY2 protein. This variant is present in population databases (rs201419367, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with multiple segmentation defects (PMID: 25343988). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 221271). 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. -
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RIPPLY2: PVS1:Strong, PM2, PM3, PP4, PS3:Supporting -
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Spondylocostal dysostosis 6, autosomal recessive Pathogenic:2
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Spondylocostal dysostosis 2, autosomal recessive Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at