18-63979936-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_002640.4(SERPINB8):c.304C>T(p.Pro102Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,613,758 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (2 hom.)
• Consequence: SERPINB8 NM_002640.4 missense, splice_region
• Scores: Splicing: ADA: 0.0004203
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.637

Genes affected

SERPINB8 (HGNC:8952): (serpin family B member 8) The protein encoded by this gene is a member of the ov-serpin family of serine protease inhibitors. The encoded protein is produced by platelets and can bind to and inhibit the function of furin, a serine protease involved in platelet functions. In addition, this protein has been found to enhance the mechanical stability of cell-cell adhesion in the skin, and defects in this gene have been associated with an autosomal-recessive form of exfoliative ichthyosis. [provided by RefSeq, Jan 2017]

HMSD (HGNC:23037): (histocompatibility minor serpin domain containing) This gene encodes a serpin-domain containing protein that may function as a serine protease inhibitor. This gene is primarily expressed in cells of myeloid lineage. A polymorphism in this gene may result in the expression a splice variant that encodes a minor histocompatibility antigen. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007079184).
• BP6: Variant 18-63979936-C-T is Benign according to our data. Variant chr18-63979936-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2061790.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB8	NM_002640.4	c.304C>T	p.Pro102Ser	missense_variant, splice_region_variant	3/7	ENST00000397985.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB8	ENST00000397985.7	c.304C>T	p.Pro102Ser	missense_variant, splice_region_variant	3/7	1	NM_002640.4	P1

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 165 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00128 AC: 322 AN: 250994 Hom.: 0 AF XY: 0.00113 AC XY: 154 AN XY: 135706

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000695

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000555

Gnomad NFE exome AF: 0.00258

Gnomad OTH exome AF: 0.000654

GnomAD4 exome AF: 0.00180 AC: 2636 AN: 1461598 Hom.: 2 Cov.: 31 AF XY: 0.00178 AC XY: 1293 AN XY: 727120

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000618

Gnomad4 NFE exome AF: 0.00225

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00108 AC: 165 AN: 152160 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74324

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.00159 Hom.: 0

Bravo AF: 0.000975

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00145 AC: 176

EpiCase AF: 0.00185

EpiControl AF: 0.00178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	8.6
Dann	Benign	0.80
DEOGEN2	Benign	0.12	T;T;.;.;T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0071	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.29	N;N;.;N;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.36	N;N;.;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.66	T;T;.;T;T;T
Sift4G	Benign	0.81	T;T;.;T;T;T
Polyphen		0.0030	B;B;.;.;.;.
Vest4		0.11
MVP		0.49
MPC		0.015
ClinPred		0.0090	T
GERP RS		-0.43
Varity_R		0.050
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00042
dbscSNV1_RF	Benign	0.094
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: rs150067519; hg19: chr18-61647170; COSMIC: COSV99039552;