18-63978343-C-G

Variant names:

• chr18-63978343-C-G
• NM_002640.4:c.35C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002640.4(SERPINB8):​c.35C>G​(p.Ala12Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINB8 NM_002640.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

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_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB8	NM_002640.4	c.35C>G	p.Ala12Gly	missense_variant	Exon 2 of 7	ENST00000397985.7	NP_002631.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB8	ENST00000397985.7	c.35C>G	p.Ala12Gly	missense_variant	Exon 2 of 7	1	NM_002640.4	ENSP00000381072.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35C>G (p.A12G) alteration is located in exon 2 (coding exon 1) of the SERPINB8 gene. This alteration results from a C to G substitution at nucleotide position 35, causing the alanine (A) at amino acid position 12 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T;.;.;T;T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	.;T;T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	1.7	L;L;.;L;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D;D;.;D;D;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.017	D;D;.;D;D;D
Sift4G	Uncertain	0.0060	D;D;.;D;T;T
Polyphen		0.83	P;P;.;.;.;.
Vest4		0.61
MutPred		0.88		Loss of ubiquitination at K17 (P = 0.1741);Loss of ubiquitination at K17 (P = 0.1741);Loss of ubiquitination at K17 (P = 0.1741);Loss of ubiquitination at K17 (P = 0.1741);Loss of ubiquitination at K17 (P = 0.1741);Loss of ubiquitination at K17 (P = 0.1741);
MVP		0.95
MPC		0.047
ClinPred		0.98	D
GERP RS		4.2
Varity_R		0.54
gMVP		0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr18-61645577;