NM_005732.4:c.1202G>C
Variant summary
Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_005732.4(RAD50):c.1202G>C(p.Arg401Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R401R) has been classified as Likely benign.
Frequency
Consequence
NM_005732.4 missense
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: Likely_benign. The variant received -3 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RAD50 | ENST00000378823.8 | c.1202G>C | p.Arg401Thr | missense_variant | Exon 8 of 25 | 1 | NM_005732.4 | ENSP00000368100.4 | ||
ENSG00000283782 | ENST00000638452.2 | c.905G>C | p.Arg302Thr | missense_variant | Exon 10 of 27 | 5 | ENSP00000492349.2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000796 AC: 2AN: 251106 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461722Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727170 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74348 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 401 of the RAD50 protein (p.Arg401Thr). This variant is present in population databases (rs768858742, gnomAD 0.002%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 457366). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD50 protein function. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at