rs2295766

Variant names:

• chr6-2953160-C-T
• rs2295766
• NM_004568.6:c.457G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G153A) has been classified as Uncertain significance.

• 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
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 91

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004568.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB6	NM_004568.6	MANE Select	c.457G>A	p.Gly153Ser	missense	Exon 5 of 7	NP_004559.4
	SERPINB6	NM_001271823.2		c.514G>A	p.Gly172Ser	missense	Exon 5 of 7	NP_001258752.1	A0A087X1N8
	SERPINB6	NM_001271822.2		c.499G>A	p.Gly167Ser	missense	Exon 5 of 7	NP_001258751.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB6	ENST00000380539.7	TSL:3 MANE Select	c.457G>A	p.Gly153Ser	missense	Exon 5 of 7	ENSP00000369912.2	P35237
	SERPINB6	ENST00000380520.6	TSL:1	c.457G>A	p.Gly153Ser	missense	Exon 5 of 7	ENSP00000369891.1	P35237
	SERPINB6	ENST00000380524.5	TSL:1	c.457G>A	p.Gly153Ser	missense	Exon 5 of 7	ENSP00000369896.1	P35237

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

GnomAD2 exomes AF: 0.00408 AC: 1025 AN: 251480 AF XY: 0.00308

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 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

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0158 AC: 705 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0114 AC: 453 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1112010

Other (OTH) AF: 0.00184 AC: 111 AN: 60396

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

African (AFR) AF: 0.0000722 AC: 3 AN: 41556

American (AMR) AF: 0.00444 AC: 68 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.0193 AC: 100 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.000779 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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	SERPINB6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.85
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.18
Sift	Benign	0.045	D
Sift4G	Uncertain	0.058	T
Polyphen		0.030	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
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2295766; hg19: chr6-2953394;