rs2295766

chr6-2953160-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004568.6(SERPINB6):c.457G>A(p.Gly153Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,614,204 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00088 (13 hom.)
• Consequence: SERPINB6 NM_004568.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.853

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077928305).
• BP6: Variant 6-2953160-C-T is Benign according to our data. Variant chr6-2953160-C-T is described in ClinVar as [Benign]. Clinvar id is 44134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00117 (178/152320) while in subpopulation EAS AF= 0.0193 (100/5186). AF 95% confidence interval is 0.0162. There are 1 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6	c.457G>A	p.Gly153Ser	missense_variant	5/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7	c.457G>A	p.Gly153Ser	missense_variant	5/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes AF: 0.00116 AC: 177 AN: 152202 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00408 AC: 1025 AN: 251480 Hom.: 8 AF XY: 0.00308 AC XY: 418 AN XY: 135912

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0172

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0221

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.000876 AC: 1280 AN: 1461884 Hom.: 13 Cov.: 67 AF XY: 0.000729 AC XY: 530 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0114

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00184

GnomAD4 genome AF: 0.00117 AC: 178 AN: 152320 Hom.: 1 Cov.: 34 AF XY: 0.00113 AC XY: 84 AN XY: 74490

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00444

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000699 Hom.: 0

Bravo AF: 0.00195

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00335 AC: 407

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Gly153Ser in Exon 06 of SERPINB6: This variant is not expected to have clinical significance because it has been identified in 5.0% (5/100) of chromosomes from a population in the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP; rs 2295766). -

SERPINB6-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	4.7
Dann	Uncertain	0.98
DEOGEN2	Uncertain	0.50	T;T;T;T;T;T;T;T;T;.;T;T;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.41	N
MetaRNN	Benign	0.0078	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M;M;.;.;.;M;M;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N;N;N;N;.;N;.;.;.;.;.;N;.;.
REVEL	Benign	0.18
Sift	Benign	0.045	D;D;D;D;.;D;.;.;.;.;.;D;.;.
Sift4G	Uncertain	0.058	T;T;T;T;.;T;.;T;.;.;.;T;.;.
Polyphen		0.030	B;B;B;B;B;B;B;.;.;.;B;B;.;.
Vest4		0.15
MVP		0.88
MPC		0.30
ClinPred		0.028	T
GERP RS		0.012
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.40

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: rs2295766; hg19: chr6-2953394;