NM_002640.4:c.274C>A

Variant names:

• chr18-63979906-C-A
• rs151258628
• NM_002640.4:c.274C>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002640.4(SERPINB8):​c.274C>A​(p.Leu92Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINB8 NM_002640.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB8	NM_002640.4	c.274C>A	p.Leu92Ile	missense_variant	Exon 3 of 7	ENST00000397985.7	NP_002631.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB8	ENST00000397985.7	c.274C>A	p.Leu92Ile	missense_variant	Exon 3 of 7	1	NM_002640.4	ENSP00000381072.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251284 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0094	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T;.;.;T;T
Eigen	Benign	-0.066
Eigen_PC	Benign	-0.084
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	.;D;D;D;T;D
M_CAP	Benign	0.051	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	1.0	L;L;.;L;.;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.5	N;N;.;N;N;N
REVEL	Uncertain	0.49
Sift	Benign	0.079	T;T;.;T;D;D
Sift4G	Benign	0.099	T;T;.;T;T;T
Polyphen		0.87	P;P;.;.;.;.
Vest4		0.27
MutPred		0.79		Gain of catalytic residue at L92 (P = 0.0301);Gain of catalytic residue at L92 (P = 0.0301);Gain of catalytic residue at L92 (P = 0.0301);Gain of catalytic residue at L92 (P = 0.0301);Gain of catalytic residue at L92 (P = 0.0301);Gain of catalytic residue at L92 (P = 0.0301);
MVP		0.76
MPC		0.059
ClinPred		0.81	D
GERP RS		3.9
Varity_R		0.51
gMVP		0.43

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: rs151258628; hg19: chr18-61647140;