chr6-2948314-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_004568.6(SERPINB6):c.1115G>A(p.Arg372His) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,472 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 Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
SERPINB6
NM_004568.6 missense
NM_004568.6 missense
Scores
8
7
3
Clinical Significance
Conservation
PhyloP100: 3.92
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 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.982
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SERPINB6 | NM_004568.6 | c.1115G>A | p.Arg372His | missense_variant | 7/7 | ENST00000380539.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SERPINB6 | ENST00000380539.7 | c.1115G>A | p.Arg372His | missense_variant | 7/7 | 3 | NM_004568.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251170Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135766
GnomAD3 exomes
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461472Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727026
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
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ExAC
?
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2
Asia WGS
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1
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3478
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with SERPINB6-related conditions. This variant is present in population databases (rs748043996, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 372 of the SERPINB6 protein (p.Arg372His). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Pathogenic
DEOGEN2
Uncertain
D;D;D;D;D;D;D;T;T;.;D;D;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M;M;M;.;.;.;M;M;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D;.;D;.;.;.;.;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;.;D;.;.;.;.;.;D;.
Sift4G
Pathogenic
D;D;D;D;.;D;.;D;.;.;.;D;.
Polyphen
D;D;D;D;D;D;D;.;.;.;D;D;.
Vest4
MutPred
Loss of methylation at R372 (P = 0.0265);Loss of methylation at R372 (P = 0.0265);Loss of methylation at R372 (P = 0.0265);Loss of methylation at R372 (P = 0.0265);Loss of methylation at R372 (P = 0.0265);Loss of methylation at R372 (P = 0.0265);Loss of methylation at R372 (P = 0.0265);.;.;.;Loss of methylation at R372 (P = 0.0265);Loss of methylation at R372 (P = 0.0265);.;
MVP
MPC
0.56
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at