rs1201327476
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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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
SERPINB6
NM_004568.6 stop_gained
NM_004568.6 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.09
Genes affected
SERPINB6 (HGNC:8950): (serpin family B member 6) The protein encoded by this gene is a member of the serpin (serine proteinase inhibitor) superfamily, and ovalbumin(ov)-serpin subfamily. It was originally discovered as a placental thrombin inhibitor. The mouse homolog was found to be expressed in the hair cells of the inner ear. Mutations in this gene are associated with nonsyndromic progressive hearing loss, suggesting that this serpin plays an important role in the inner ear in the protection against leakage of lysosomal content during stress, and that loss of this protection results in cell death and sensorineural hearing loss. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.4 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-2948964-C-A is Pathogenic according to our data. Variant chr6-2948964-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 506010.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SERPINB6 | NM_004568.6 | c.679G>T | p.Glu227* | stop_gained | 6/7 | ENST00000380539.7 | NP_004559.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SERPINB6 | ENST00000380539.7 | c.679G>T | p.Glu227* | stop_gained | 6/7 | 3 | NM_004568.6 | ENSP00000369912.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251496Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135922
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727246
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Rare genetic deafness Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 03, 2017 | 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
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -50
Find out detailed SpliceAI scores and Pangolin per-transcript scores at