6-2948488-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_004568.6(SERPINB6):c.941A>G(p.Lys314Arg) 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 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 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: 1.07

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.307441).
• BP6: Variant 6-2948488-T-C is Benign according to our data. Variant chr6-2948488-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227939.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6	c.941A>G	p.Lys314Arg	missense_variant	7/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7	c.941A>G	p.Lys314Arg	missense_variant	7/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727244

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

Jul 20, 2015

p.Lys314Arg in exon 8 of SERPINB6: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. O f note, five mammals, including dolphin, killer whale, cat, ferret, and Pacific walrus, have an Arginine (Arg) at this position despite high nearby amino acid c onservation. Additional computational prediction tools do not suggest a high lik elihood of impact to the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	15
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;T;T;T;T;T;T;.;T;T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.48	N
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.31	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;M;M;M;M;M;.;.;.;M;M;.
MutationTaster	Benign	0.91	N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-2.2	N;N;N;N;.;N;.;.;.;.;.;N;.
REVEL	Benign	0.22
Sift	Benign	0.051	T;T;T;T;.;T;.;.;.;.;.;T;.
Sift4G	Uncertain	0.060	T;T;T;T;.;T;.;T;.;.;.;T;.
Polyphen		0.051	B;B;B;B;B;B;B;.;.;.;B;B;.
Vest4		0.091
MutPred		0.57		Loss of methylation at K314 (P = 0.0355);Loss of methylation at K314 (P = 0.0355);Loss of methylation at K314 (P = 0.0355);Loss of methylation at K314 (P = 0.0355);Loss of methylation at K314 (P = 0.0355);Loss of methylation at K314 (P = 0.0355);Loss of methylation at K314 (P = 0.0355);.;.;.;Loss of methylation at K314 (P = 0.0355);Loss of methylation at K314 (P = 0.0355);.;
MVP		0.88
MPC		0.085
ClinPred		0.22	T
GERP RS		0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs876657582; hg19: chr6-2948722;