chr5-132638223-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_005732.4(RAD50):c.3618G>T(p.Lys1206Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1206R) has been classified as Uncertain significance.
Frequency
Consequence
NM_005732.4 missense, splice_region
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD50 | NM_005732.4 | c.3618G>T | p.Lys1206Asn | missense_variant, splice_region_variant | 23/25 | ENST00000378823.8 | |
TH2LCRR | NR_132124.1 | n.88C>A | non_coding_transcript_exon_variant | 2/3 | |||
TH2LCRR | NR_132125.1 | n.232C>A | non_coding_transcript_exon_variant | 3/3 | |||
TH2LCRR | NR_132126.1 | n.217C>A | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.3618G>T | p.Lys1206Asn | missense_variant, splice_region_variant | 23/25 | 1 | NM_005732.4 | P1 | |
TH2LCRR | ENST00000435042.1 | n.325C>A | non_coding_transcript_exon_variant | 4/4 | 5 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251216Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135770
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461824Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727218
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74292
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Apr 29, 2017 | In summary, this is a novel missense change with uncertain impact on splicing and protein function. It has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098) but according to multiple splice site algorithms this particular variant is not predicted to significantly affect splicing. These predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RAD50-related disease. This sequence change replaces lysine with asparagine at codon 1206 of the RAD50 protein (p.Lys1206Asn). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and asparagine. This variant also falls at the last nucleotide of exon 23 of the RAD50 coding sequence, which is part of the consensus splice site for this exon. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at