rs764122619
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_005732.4(RAD50):c.756+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000437 in 1,603,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_005732.4 splice_donor, intron
Scores
Clinical Significance
Conservation
Publications
- Nijmegen breakage syndrome-like disorderInheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.756+2T>C | splice_donor_variant, intron_variant | Intron 5 of 24 | 1 | NM_005732.4 | ENSP00000368100.4 | |||
ENSG00000283782 | ENST00000638452.2 | c.459+2T>C | splice_donor_variant, intron_variant | Intron 7 of 26 | 5 | ENSP00000492349.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000400 AC: 1AN: 249858 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000345 AC: 5AN: 1451224Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3AN XY: 722802 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342 show subpopulations
ClinVar
Submissions by phenotype
not provided Pathogenic:2
Classification criteria: PVS1, PM2_Supporting -
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Hereditary cancer-predisposing syndrome Pathogenic:2
This sequence change affects a donor splice site in intron 5 of the RAD50 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs764122619, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 185222). Studies have shown that disruption of this splice site results in skipping of exon 5 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
The c.756+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 5 in the RAD50 gene. This alteration was identified in an individual who underwent hereditary cancer multi-gene panel testing (LaDuca H et al. Genet. Med., 2014 Nov;16:830-7). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -
Nijmegen breakage syndrome-like disorder Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at