rs397516637

Positions:

• chr6-2954679-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_004568.6(SERPINB6):​c.343C>G​(p.Gln115Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SERPINB6 NM_004568.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0900

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13769966).
• BP6: Variant 6-2954679-G-C is Benign according to our data. Variant chr6-2954679-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 44133.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-2954679-G-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6	c.343C>G	p.Gln115Glu	missense_variant	4/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7	c.343C>G	p.Gln115Glu	missense_variant	4/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 25, 2013

Gln115Glu in exon 5 of SERPINB6: This variant is not expected to have clinical s ignificance because this amino acid is not conserved among mammals and several s pecies, including rat, mouse, and tree shrew, carry a glutamic acid (Glu) at thi s position. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.42
DEOGEN2	Benign	0.12	T;T;T;T;T;T;T;T;T;.;T;T;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.73	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.14	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.80	N;N;N;N;N;N;N;.;.;.;N;N;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.28	N;N;N;N;.;N;.;.;.;.;.;N;.;.
REVEL	Benign	0.16
Sift	Benign	1.0	T;T;T;T;.;T;.;.;.;.;.;T;.;.
Sift4G	Benign	1.0	T;T;T;T;.;T;.;T;.;.;.;T;.;.
Polyphen		0.0010	B;B;B;B;B;B;B;.;.;.;B;B;.;.
Vest4		0.13
MutPred		0.47		Loss of ubiquitination at K112 (P = 0.0811);Loss of ubiquitination at K112 (P = 0.0811);Loss of ubiquitination at K112 (P = 0.0811);Loss of ubiquitination at K112 (P = 0.0811);Loss of ubiquitination at K112 (P = 0.0811);Loss of ubiquitination at K112 (P = 0.0811);Loss of ubiquitination at K112 (P = 0.0811);.;.;.;Loss of ubiquitination at K112 (P = 0.0811);Loss of ubiquitination at K112 (P = 0.0811);.;.;
MVP		0.75
MPC		0.11
ClinPred		0.034	T
GERP RS		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.21

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: rs397516637; hg19: chr6-2954913;