15-52124617-G-T
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_016194.4(GNB5):c.1032C>A(p.Tyr344*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,628 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 Likely pathogenic (★★).
Frequency
Consequence
NM_016194.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GNB5 | NM_016194.4 | c.1032C>A | p.Tyr344* | stop_gained | Exon 12 of 13 | ENST00000261837.12 | NP_057278.2 | |
GNB5 | NM_006578.4 | c.906C>A | p.Tyr302* | stop_gained | Exon 10 of 11 | NP_006569.1 | ||
GNB5 | NM_001379343.1 | c.750C>A | p.Tyr250* | stop_gained | Exon 10 of 11 | NP_001366272.1 | ||
GNB5 | XM_011521162.4 | c.906C>A | p.Tyr302* | stop_gained | Exon 10 of 11 | XP_011519464.1 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251104Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135694
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461628Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5AN XY: 727110
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Gnb5-related intellectual disability-cardiac arrhythmia syndrome Pathogenic:2Other:1
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Recurrent variant reported in 2 families from Pakistan; de novo in 1 family -
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not provided Pathogenic:1
The c.1032 C>A nucleotide substitution, resulting in the Y344X variant in the GNB5 gene, has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. However, a different nucleotide substitution (c.1032 C>G) that also results in the Y344X variant, denoted as c.906 C>G and Y320X due to alternative nomenclature, was reported previously as homozygous in an Indian child with severe intellectual disability, absent speech, epilepsy, hypotonia, gastric reflux, nystagmus, and severe sick sinus syndrome (Lodder et al., 2016). The Y344X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y344X variant due to the c.1032 C>A substitution is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret Y344X as a pathogenic variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at