rs2236277

Positions:

• chr6-2959279-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004568.6(SERPINB6):​c.54G>A​(p.Thr18Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,613,822 control chromosomes in the GnomAD database, including 83,768 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7294 hom., cov: 32)
  • Exomes 𝑓: 0.32 (76474 hom.)
• Consequence: SERPINB6 NM_004568.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.58

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 6-2959279-C-T is Benign according to our data. Variant chr6-2959279-C-T is described in ClinVar as [Benign]. Clinvar id is 44135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-2959279-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB6	NM_004568.6	c.54G>A	p.Thr18Thr	synonymous_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.54G>A	p.Thr18Thr	synonymous_variant	2/7	3	NM_004568.6	ENSP00000369912.2

Frequencies

GnomAD3 genomes AF: 0.296 AC: 44912 AN: 151954 Hom.: 7291 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.388

Gnomad ASJ AF: 0.373

Gnomad EAS AF: 0.500

Gnomad SAS AF: 0.356

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.338

GnomAD3 exomes AF: 0.349 AC: 87707 AN: 251466 Hom.: 16340 AF XY: 0.344 AC XY: 46740 AN XY: 135908

Gnomad AFR exome AF: 0.174

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.380

Gnomad EAS exome AF: 0.501

Gnomad SAS exome AF: 0.335

Gnomad FIN exome AF: 0.278

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.346

GnomAD4 exome AF: 0.319 AC: 466494 AN: 1461752 Hom.: 76474 Cov.: 39 AF XY: 0.319 AC XY: 232322 AN XY: 727186

Gnomad4 AFR exome AF: 0.168

Gnomad4 AMR exome AF: 0.481

Gnomad4 ASJ exome AF: 0.375

Gnomad4 EAS exome AF: 0.498

Gnomad4 SAS exome AF: 0.334

Gnomad4 FIN exome AF: 0.282

Gnomad4 NFE exome AF: 0.310

Gnomad4 OTH exome AF: 0.322

GnomAD4 genome AF: 0.295 AC: 44914 AN: 152070 Hom.: 7294 Cov.: 32 AF XY: 0.296 AC XY: 21996 AN XY: 74340

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.388

Gnomad4 ASJ AF: 0.373

Gnomad4 EAS AF: 0.500

Gnomad4 SAS AF: 0.355

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.320

Gnomad4 OTH AF: 0.336

Alfa AF: 0.325 Hom.: 13729

Bravo AF: 0.303

Asia WGS AF: 0.387 AC: 1342 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr18Thr in Exon 03 of SERPINB6: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 32.1% (2253/7020) of European American chromosomes from a broad population by the NHLBI Exome Sequ encing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2236277). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 91 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.1
DANN	Benign	0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs2236277; hg19: chr6-2959513; COSMIC: COSV59565112; COSMIC: COSV59565112;