18-63987098-CA-CAA

Variant names:

• chr18-63987098-C-CA
• rs762923677
• NM_002640.4:c.947dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_002640.4(SERPINB8):​c.947dupA​(p.Cys317ValfsTer7) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. 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 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.13
• Publications: 0 publications found

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]

SERPINB8 Gene-Disease associations (from GenCC):

• peeling skin syndrome 5

  Inheritance: AD, Unknown, AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, G2P
• exfoliative ichthyosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.157 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002640.4. 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
	SERPINB8	NM_002640.4	MANE Select	c.947dupA	p.Cys317ValfsTer7	frameshift	Exon 7 of 7	NP_002631.3
	SERPINB8	NM_001366198.1		c.947dupA	p.Cys317ValfsTer7	frameshift	Exon 7 of 7	NP_001353127.1	P50452-1
	SERPINB8	NM_198833.2		c.947dupA	p.Cys317ValfsTer7	frameshift	Exon 7 of 7	NP_942130.1	P50452-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINB8	ENST00000397985.7	TSL:1 MANE Select	c.947dupA	p.Cys317ValfsTer7	frameshift	Exon 7 of 7	ENSP00000381072.2	P50452-1
	SERPINB8	ENST00000353706.6	TSL:5	c.947dupA	p.Cys317ValfsTer7	frameshift	Exon 7 of 7	ENSP00000331368.3	P50452-1
	SERPINB8	ENST00000858461.1		c.947dupA	p.Cys317ValfsTer7	frameshift	Exon 7 of 7	ENSP00000528520.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs762923677;

hg19: chr18-61654332;