rs201080069
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_004568.6(SERPINB6):c.430+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00031 in 1,604,420 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00032 ( 3 hom. )
Consequence
SERPINB6
NM_004568.6 splice_donor_region, intron
NM_004568.6 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.0002101
2
Clinical Significance
Conservation
PhyloP100: 0.0530
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_benign. Variant got -3 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
?
Variant 6-2954589-C-T is Benign according to our data. Variant chr6-2954589-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165191.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr6-2954589-C-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINB6 | NM_004568.6 | c.430+3G>A | splice_donor_region_variant, intron_variant | ENST00000380539.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINB6 | ENST00000380539.7 | c.430+3G>A | splice_donor_region_variant, intron_variant | 3 | NM_004568.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000256 AC: 39AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000454 AC: 114AN: 251366Hom.: 0 AF XY: 0.000567 AC XY: 77AN XY: 135864
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GnomAD4 exome AF: 0.000316 AC: 459AN: 1452156Hom.: 3 Cov.: 28 AF XY: 0.000372 AC XY: 269AN XY: 723090
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 02, 2022 | This sequence change falls in intron 4 of the SERPINB6 gene. It does not directly change the encoded amino acid sequence of the SERPINB6 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201080069, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SERPINB6-related conditions. ClinVar contains an entry for this variant (Variation ID: 165191). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2019 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 29, 2013 | c.430+3G>A in Intron 5 SERPINB6: This variant is not expected to have clinical s ignificance because splice prediction algorithms do not predict an impact to spl icing and the variant has been identified in 0.2% (29/16492) of South Asian chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs201080069). - |
Autosomal recessive nonsyndromic hearing loss 91 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital | Feb 25, 2020 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at