15-51471365-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP5
The ENST00000560891.6(DMXL2):c.7250G>A(p.Arg2417His) variant causes a missense change. The variant allele was found at a frequency of 0.0000217 in 1,613,218 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2417C) has been classified as Likely benign.
Frequency
Consequence
ENST00000560891.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DMXL2 | NM_001378457.1 | c.7250G>A | p.Arg2417His | missense_variant | 29/44 | ENST00000560891.6 | NP_001365386.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DMXL2 | ENST00000560891.6 | c.7250G>A | p.Arg2417His | missense_variant | 29/44 | 1 | NM_001378457.1 | ENSP00000453267 | A1 | |
ENST00000561007.1 | n.494+4836C>T | intron_variant, non_coding_transcript_variant | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 151952Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251084Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135690
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461266Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 726918
GnomAD4 genome AF: 0.0000263 AC: 4AN: 151952Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74178
ClinVar
Submissions by phenotype
Hearing loss, autosomal dominant 71 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | research | King Laboratory, University of Washington | Feb 28, 2023 | This variant occurred in heterozygosity in a patient with bilateral sensorineural hearing loss of onset <18 years within a single family, in a study of pediatric hearing loss conducted by the King Laboratory (Carlson RJ et al. JAMA-OtoHNS 2023). This patient’s family has no other history of hearing loss. This variant is a missense at a completely conserved site and is predicted to be damaging by multiple in-silico tools. As of January 2023, this variant has been reported to ClinVar as likely pathogenic and is found in 9 heterozygotes on gnomAD. Based on consistently predicted functional effect, literature evidence of pathogenicity, and goodness of fit of genotype to phenotype, we conclude that this variant is likely pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 05, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2417 of the DMXL2 protein (p.Arg2417His). This variant is present in population databases (rs754786373, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal dominant non-syndromic hearing loss (PMID: 27657680). ClinVar contains an entry for this variant (Variation ID: 431430). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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