rs147962494

Positions:

• chr6-2959208-T-C
• chr6-2959208-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004568.6(SERPINB6):​c.125A>G​(p.Tyr42Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y42S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINB6 NM_004568.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0560

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]

SERPINB6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33125055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB6	NM_004568.6	c.125A>G	p.Tyr42Cys	missense_variant	2/7	ENST00000380539.7	NP_004559.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB6	ENST00000380539.7	c.125A>G	p.Tyr42Cys	missense_variant	2/7	3	NM_004568.6	ENSP00000369912.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	20
DANN	Benign	0.85
DEOGEN2	Uncertain	0.55	D;D;D;D;D;D;D;T;T;D;D;T;.;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.085	N
LIST_S2	Benign	0.75	.;.;.;.;.;.;.;T;.;.;T;T;.;T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;.;.;M;M;.;.;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N;N;N;N;.;N;.;.;.;.;N;.;.;.;.;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0090	D;D;D;D;.;D;.;.;.;.;D;.;.;.;.;.
Sift4G	Uncertain	0.036	D;D;D;D;.;D;.;D;.;.;D;.;.;.;.;.
Polyphen		0.84	P;P;P;P;P;P;P;.;.;P;P;.;.;.;.;.
Vest4		0.27
MutPred		0.66		Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);.;.;Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);.;Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);Gain of catalytic residue at M40 (P = 0.0026);
MVP		0.66
MPC		0.44
ClinPred		0.45	T
GERP RS		-4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs147962494; hg19: chr6-2959442;