rs876657997

Positions:

• chr6-2953114-T-C

Variant summary

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

The NM_004568.6(SERPINB6):​c.503A>G​(p.Tyr168Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 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: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINB6 NM_004568.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.77

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, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB6	NM_004568.6	c.503A>G	p.Tyr168Cys	missense_variant	5/7	ENST00000380539.7	NP_004559.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB6	ENST00000380539.7	c.503A>G	p.Tyr168Cys	missense_variant	5/7	3	NM_004568.6	ENSP00000369912	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461890 Hom.: 0 Cov.: 68 AF XY: 0.00 AC XY: 0 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 27, 2015

The p.Tyr168Cys variant in SERPINB6 has not been previously reported in individu als with hearing loss and was absent from large population studies. Computationa l prediction tools and conservation analyses suggest that the Tyr168Cys variant may impact the protein, though this information is not predictive enough to dete rmine pathogenicity. In summary, the clinical significance of the p.Tyr168Cys va riant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;D;D;D;D;D;T;T;.;D;D;T;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;.;.;.;.;.;D;.;D;.;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.7	H;H;H;H;H;H;H;.;.;.;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-8.3	D;D;D;D;.;D;.;.;.;.;.;D;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;D;D;D;.;D;.;.;.;.;.;D;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;.;D;.;D;.;.;.;D;.;.
Polyphen		1.0	D;D;D;D;D;D;D;.;.;.;D;D;.;.
Vest4		0.94
MutPred		0.95		Loss of phosphorylation at Y168 (P = 0.1271);Loss of phosphorylation at Y168 (P = 0.1271);Loss of phosphorylation at Y168 (P = 0.1271);Loss of phosphorylation at Y168 (P = 0.1271);Loss of phosphorylation at Y168 (P = 0.1271);Loss of phosphorylation at Y168 (P = 0.1271);Loss of phosphorylation at Y168 (P = 0.1271);.;.;.;Loss of phosphorylation at Y168 (P = 0.1271);Loss of phosphorylation at Y168 (P = 0.1271);.;.;
MVP		0.96
MPC		0.56
ClinPred		1.0	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs876657997; hg19: chr6-2953348;