rs376306240
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_031885.5(BBS2):c.401C>G(p.Pro134Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,882 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P134S) has been classified as Uncertain significance.
Frequency
Consequence
NM_031885.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BBS2 | NM_031885.5 | c.401C>G | p.Pro134Arg | missense_variant | 3/17 | ENST00000245157.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BBS2 | ENST00000245157.11 | c.401C>G | p.Pro134Arg | missense_variant | 3/17 | 1 | NM_031885.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152146Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251422Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135876
GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461736Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727180
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74318
ClinVar
Submissions by phenotype
Bardet-Biedl syndrome 2 Pathogenic:3Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 08, 2021 | NM_031885.3(BBS2):c.401C>G(P134R) is a missense variant classified as a variant of uncertain significance in the context of Bardet-Biedl syndrome, BBS2-related. P134R has not been observed in cases with relevant disease. Functional assessments of this variant are available in the literature (PMID: DeBenedictis_2020_(no PMID; article), Perkins_2015_(no PMID; abstract)). P134R has been observed in population frequency databases (gnomAD: OTH 0.02%). In summary, there is insufficient evidence to classify NM_031885.3(BBS2):c.401C>G(P134R) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 10, 2023 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 13, 2021 | - - |
Retinitis pigmentosa 74 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2015 | - - |
Retinal dystrophy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 29, 2019 | - - |
Bardet-Biedl syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 134 of the BBS2 protein (p.Pro134Arg). This variant is present in population databases (rs376306240, gnomAD 0.01%). This missense change has been observed in individual(s) with retinitis pigmentosa (PMID: 25541840, 31877679). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209043). 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 BBS2 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. - |
Retinitis pigmentosa Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Sharon lab, Hadassah-Hebrew University Medical Center | Jun 23, 2019 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at