rs1201327476
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_004568.6(SERPINB6):c.679G>T(p.Glu227*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,892 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_004568.6 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SERPINB6 | NM_004568.6 | c.679G>T | p.Glu227* | stop_gained | Exon 6 of 7 | ENST00000380539.7 | NP_004559.4 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251496Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727246
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Rare genetic deafness Pathogenic:1
The p.Glu227X variant in SERPINB6 has not been previously reported in individual s with hearing loss, but has been identified in 1/17248 East Asian chromosomes b y the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org). A lthough this variant has been seen in the general population, its frequency is l ow enough to be consistent with a recessive carrier frequency. This nonsense var iant leads to a premature termination codon at position 227, which is predicted to lead to a truncated or absent protein. There is moderate evidence suggesting that truncating variants in SERPINB6 result in autosomal recessive hearing loss. One report describes a consanguineous family that were homozygous for a nonsens e variant (p.Glu245X) which segregated with hearing loss in four affected family members, and SERPINB6 protein expression was absent in leukocytes of homozygote s (Sirmaci 2010). Another study reported a proband with hearing loss who was com pound heterozygous for a frameshift and a canonical splice site variant (Kim 201 5). In addition, the SERPINB6 protein was also shown to be expressed in the mous e inner ear (Sirmaci 2010), and a knockout mouse model was shown to display hear ing loss and progressive cellular degeneration in the cochlea (Tan 2013). In sum mary, although additional evidence is needed to further support the gene-disease association, the p.Gly227X variant in SERPINB6 is likely pathogenic for autosom al recessive hearing loss. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at