rs777893707
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_015340.4(LARS2):c.2572C>A(p.Gln858Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000453 in 1,612,044 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_015340.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
LARS2 | NM_015340.4 | c.2572C>A | p.Gln858Lys | missense_variant | 22/22 | ENST00000645846.2 | |
LARS2 | NM_001368263.1 | c.2572C>A | p.Gln858Lys | missense_variant | 21/21 | ||
LARS2 | XM_017006042.2 | c.*29C>A | 3_prime_UTR_variant | 21/21 | |||
LARS2 | XM_047447830.1 | c.*29C>A | 3_prime_UTR_variant | 20/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
LARS2 | ENST00000645846.2 | c.2572C>A | p.Gln858Lys | missense_variant | 22/22 | NM_015340.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000282 AC: 7AN: 248598Hom.: 0 AF XY: 0.0000297 AC XY: 4AN XY: 134478
GnomAD4 exome AF: 0.0000486 AC: 71AN: 1459742Hom.: 0 Cov.: 31 AF XY: 0.0000523 AC XY: 38AN XY: 726256
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152302Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74480
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2020 | Observed in a patient with suspected mitochondrial disease in published literature (Nogueira et al., 2019); however, this patient did not have hearing loss; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30831263) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 12, 2021 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 28, 2016 | Variant classified as Uncertain Significance - Favor Benign. The p.Gln858Lys var iant in LARS2 has not been previously reported in individuals with hearing loss, but has been identified in 6/66474 European chromosomes by the Exome Aggregatio n Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs777893707). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. The glutamine (Gln) residue at position 8 58 is not conserved in mammals or evolutionarily distant species and one mammal (tenrec) carries a lysine (Lys), supporting that the change at this position may be tolerated. Additional computational prediction tools suggest that the p.Gln 858Lys variant may not impact the protein, though this information is not predic tive enough to rule out pathogenicity. In summary, while the clinical significan ce of the p.Gln858Lys variant is uncertain, available data suggest that it is mo re likely to be benign. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 13, 2022 | The c.2572C>A (p.Q858K) alteration is located in exon 22 (coding exon 20) of the LARS2 gene. This alteration results from a C to A substitution at nucleotide position 2572, causing the glutamine (Q) at amino acid position 858 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at