chr6-2948334-G-A

Variant names:

• chr6-2948334-G-A
• rs145397970
• NM_004568.6:c.1095C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004568.6(SERPINB6):​c.1095C>T​(p.Asn365Asn) 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
• Publications: 2 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: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.016).
• BP6: Variant 6-2948334-G-A is Benign according to our data. Variant chr6-2948334-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 165188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-7.36 with no splicing effect.

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.1095C>T	p.Asn365Asn	synonymous	Exon 7 of 7	NP_004559.4
	SERPINB6	NM_001271823.2		c.1152C>T	p.Asn384Asn	synonymous	Exon 7 of 7	NP_001258752.1	A0A087X1N8
	SERPINB6	NM_001271822.2		c.1137C>T	p.Asn379Asn	synonymous	Exon 7 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.1095C>T	p.Asn365Asn	synonymous	Exon 7 of 7	ENSP00000369912.2	P35237
	SERPINB6	ENST00000380520.6	TSL:1	c.1095C>T	p.Asn365Asn	synonymous	Exon 7 of 7	ENSP00000369891.1	P35237
	SERPINB6	ENST00000380524.5	TSL:1	c.1095C>T	p.Asn365Asn	synonymous	Exon 7 of 7	ENSP00000369896.1	P35237

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

GnomAD2 exomes AF: 0.00142 AC: 357 AN: 251292 AF XY: 0.00142

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 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

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

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

East Asian (EAS) AF: 0.000327 AC: 13 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00461 AC: 246 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00180 AC: 2006 AN: 1111986

Other (OTH) AF: 0.00106 AC: 64 AN: 60380

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

African (AFR) AF: 0.000193 AC: 8 AN: 41558

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00135 AC: 92 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00111 Hom.: 0

Bravo AF: 0.000703

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.18
DANN	Benign	0.60
PhyloP100		-7.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs145397970; hg19: chr6-2948568; COSMIC: COSV59564777; COSMIC: COSV59564777;