6-2955596-G-A

Position:

• chr6-2955596-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004568.6(SERPINB6):​c.240C>T​(p.Asn80=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,198 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0088 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00092 (22 hom.)
• Consequence: SERPINB6 NM_004568.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.663

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 6-2955596-G-A is Benign according to our data. Variant chr6-2955596-G-A is described in ClinVar as [Benign]. Clinvar id is 178631.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.663 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00884 (1346/152340) while in subpopulation AFR AF= 0.0309 (1283/41572). AF 95% confidence interval is 0.0295. There are 21 homozygotes in gnomad4. There are 613 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6	c.240C>T	p.Asn80=	synonymous_variant	3/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7	c.240C>T	p.Asn80=	synonymous_variant	3/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes AF: 0.00882 AC: 1343 AN: 152222 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00233 AC: 586 AN: 251494 Hom.: 12 AF XY: 0.00162 AC XY: 220 AN XY: 135920

Gnomad AFR exome AF: 0.0337

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000924 AC: 1351 AN: 1461858 Hom.: 22 Cov.: 32 AF XY: 0.000769 AC XY: 559 AN XY: 727240

Gnomad4 AFR exome AF: 0.0345

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000369

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.00884 AC: 1346 AN: 152340 Hom.: 21 Cov.: 33 AF XY: 0.00823 AC XY: 613 AN XY: 74494

Gnomad4 AFR AF: 0.0309

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00389 Hom.: 6

Bravo AF: 0.0100

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2012

Asn80Asn in Exon 04 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 3.1% (116/3738) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs35826070). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	3.0
DANN	Benign	0.41

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: rs35826070; hg19: chr6-2955830;