6-2948548-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_004568.6(SERPINB6):c.881C>A(p.Ala294Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,886 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: 0.0000034 (0 hom.)
• Consequence: SERPINB6 NM_004568.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

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]

ACMG classification

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, 0.969

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6	c.881C>A	p.Ala294Asp	missense_variant	7/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7	c.881C>A	p.Ala294Asp	missense_variant	7/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251492 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 30, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.026	T
BayesDel_noAF	Uncertain	0.090
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D;D;D;D;D;D;T;T;.;D;D;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.080
FATHMM_MKL	Benign	0.53	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	4.3	H;H;H;H;H;H;H;.;.;.;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-5.1	D;D;D;D;.;D;.;.;.;.;.;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;D;D;D;.;D;.;.;.;.;.;D;.
Sift4G	Uncertain	0.0040	D;D;D;D;.;D;.;D;.;.;.;D;.
Polyphen		0.99	D;D;D;D;D;D;D;.;.;.;D;D;.
Vest4		0.81
MutPred		0.87		Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);.;.;.;Gain of disorder (P = 0.026);Gain of disorder (P = 0.026);.;
MVP		0.96
MPC		0.61
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756395142; hg19: chr6-2948782; COSMIC: COSV100177809; COSMIC: COSV100177809;