rs2295769

Variant names:

• chr6-2955568-T-C
• rs2295769
• NM_004568.6:c.268A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001271823.2(SERPINB6):​c.325A>G​(p.Met109Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,613,874 control chromosomes in the GnomAD database, including 68,999 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4689 hom., cov: 33)
  • Exomes 𝑓: 0.29 (64310 hom.)
• Consequence: SERPINB6 NM_001271823.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.23
• Publications: 44 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: Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• 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=0.016168445).
• BP6: Variant 6-2955568-T-C is Benign according to our data. Variant chr6-2955568-T-C is described in ClinVar as Benign. ClinVar VariationId is 44132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271823.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB6	NM_004568.6	MANE Select	c.268A>G	p.Met90Val	missense	Exon 3 of 7	NP_004559.4
	SERPINB6	NM_001271823.2		c.325A>G	p.Met109Val	missense	Exon 3 of 7	NP_001258752.1
	SERPINB6	NM_001271822.2		c.310A>G	p.Met104Val	missense	Exon 3 of 7	NP_001258751.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB6	ENST00000380539.7	TSL:3 MANE Select	c.268A>G	p.Met90Val	missense	Exon 3 of 7	ENSP00000369912.2
	SERPINB6	ENST00000380520.6	TSL:1	c.268A>G	p.Met90Val	missense	Exon 3 of 7	ENSP00000369891.1
	SERPINB6	ENST00000380524.5	TSL:1	c.268A>G	p.Met90Val	missense	Exon 3 of 7	ENSP00000369896.1

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34590 AN: 152072 Hom.: 4682 Cov.: 33

Gnomad AFR AF: 0.0709

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.264

Gnomad ASJ AF: 0.327

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.288

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.253

Gnomad NFE AF: 0.301

Gnomad OTH AF: 0.234

GnomAD2 exomes AF: 0.266 AC: 66825 AN: 251472 AF XY: 0.275

Gnomad AFR exome AF: 0.0634

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.328

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.298

Gnomad OTH exome AF: 0.293

GnomAD4 exome AF: 0.292 AC: 427371 AN: 1461684 Hom.: 64310 Cov.: 36 AF XY: 0.294 AC XY: 213967 AN XY: 727156

African (AFR) AF: 0.0639 AC: 2138 AN: 33472

American (AMR) AF: 0.220 AC: 9822 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 8538 AN: 26134

East Asian (EAS) AF: 0.264 AC: 10481 AN: 39700

South Asian (SAS) AF: 0.307 AC: 26511 AN: 86248

European-Finnish (FIN) AF: 0.239 AC: 12769 AN: 53412

Middle Eastern (MID) AF: 0.327 AC: 1886 AN: 5766

European-Non Finnish (NFE) AF: 0.304 AC: 337825 AN: 1111838

Other (OTH) AF: 0.288 AC: 17401 AN: 60390

GnomAD4 genome AF: 0.227 AC: 34598 AN: 152190 Hom.: 4689 Cov.: 33 AF XY: 0.227 AC XY: 16893 AN XY: 74406

African (AFR) AF: 0.0708 AC: 2941 AN: 41524

American (AMR) AF: 0.264 AC: 4031 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 1135 AN: 3470

East Asian (EAS) AF: 0.267 AC: 1383 AN: 5178

South Asian (SAS) AF: 0.289 AC: 1394 AN: 4830

European-Finnish (FIN) AF: 0.229 AC: 2418 AN: 10582

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.301 AC: 20444 AN: 67996

Other (OTH) AF: 0.239 AC: 505 AN: 2112

Alfa AF: 0.277 Hom.: 23913

Bravo AF: 0.220

TwinsUK AF: 0.318 AC: 1179

ALSPAC AF: 0.302 AC: 1162

ESP6500AA AF: 0.0660 AC: 291

ESP6500EA AF: 0.299 AC: 2574

ExAC AF: 0.264 AC: 32100

Asia WGS AF: 0.275 AC: 957 AN: 3478

EpiCase AF: 0.309

EpiControl AF: 0.303

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Autosomal recessive nonsyndromic hearing loss 91 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.39
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.67	N
PhyloP100		2.2
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.19
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.016
MPC		0.097
ClinPred		0.0083	T
GERP RS		3.8
Varity_R		0.067
gMVP		0.17
Mutation Taster		=100/0	polymorphism (auto)

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: rs2295769; hg19: chr6-2955802; COSMIC: COSV59565275; COSMIC: COSV59565275;