chr11-72293422-C-T
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_030813.6(CLPB):c.2069G>A(p.Arg690His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000644 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign 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. R690C) has been classified as Uncertain significance.
Frequency
Consequence
NM_030813.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CLPB | NM_030813.6 | c.2069G>A | p.Arg690His | missense_variant | 17/17 | ENST00000294053.9 | |
CLPB | NM_001258392.3 | c.1979G>A | p.Arg660His | missense_variant | 16/16 | ENST00000538039.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CLPB | ENST00000294053.9 | c.2069G>A | p.Arg690His | missense_variant | 17/17 | 1 | NM_030813.6 | P4 | |
CLPB | ENST00000538039.6 | c.1979G>A | p.Arg660His | missense_variant | 16/16 | 2 | NM_001258392.3 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152144Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251400Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135886
GnomAD4 exome AF: 0.0000670 AC: 98AN: 1461866Hom.: 0 Cov.: 31 AF XY: 0.0000770 AC XY: 56AN XY: 727234
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74314
ClinVar
Submissions by phenotype
3-methylglutaconic aciduria, type VIIB Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 690 of the CLPB protein (p.Arg690His). This variant is present in population databases (rs758613799, gnomAD 0.008%). This variant has not been reported in the literature in individuals affected with CLPB-related conditions. ClinVar contains an entry for this variant (Variation ID: 954673). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at