rs145397970

chr6-2948334-G-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_004568.6(SERPINB6):c.1095C>T(p.Asn365=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00154 in 1,614,120 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00097 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (1 hom.)
• Consequence: SERPINB6 NM_004568.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -7.36

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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 6-2948334-G-A is Benign according to our data. Variant chr6-2948334-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 165188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-2948334-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-7.36 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6	c.1095C>T	p.Asn365=	synonymous_variant	7/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7	c.1095C>T	p.Asn365=	synonymous_variant	7/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes AF: 0.000966 AC: 147 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00135

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00142 AC: 357 AN: 251292 Hom.: 0 AF XY: 0.00142 AC XY: 193 AN XY: 135836

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00420

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00160 AC: 2344 AN: 1461822 Hom.: 1 Cov.: 32 AF XY: 0.00151 AC XY: 1099 AN XY: 727210

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00461

Gnomad4 NFE exome AF: 0.00180

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.000965 AC: 147 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74466

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00135

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000703

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 11, 2015

p.Asn365Asn in Exon 08 of SERPINB6: This variant is not expected to have clinica l significance because it does not alter an amino acid residue, is not located w ithin the splice consensus sequence, and has been identified in 0.3% (23/5696) F innish chromosomes and in 0.2% (156/66564) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs145397970) . -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Nov 06, 2023

- -

SERPINB6-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 18, 2019

This variant is classified as likely 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
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.18
Dann	Benign	0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs145397970; hg19: chr6-2948568; COSMIC: COSV59564777; COSMIC: COSV59564777;