18-63493087-G-C

Variant names:

• chr18-63493087-G-C
• rs2289520
• NM_002639.5:c.559G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002639.5(SERPINB5):​c.559G>C​(p.Val187Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 1,613,780 control chromosomes in the GnomAD database, including 20,558 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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: 𝑓 0.22 (7286 hom., cov: 32)
  • Exomes 𝑓: 0.093 (13272 hom.)
• Consequence: SERPINB5 NM_002639.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.330
• Publications: 27 publications found

Genes affected

SERPINB5 (HGNC:8949): (serpin family B member 5) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to act upstream of or within several processes, including extracellular matrix organization; prostate gland morphogenesis; and regulation of epithelial cell proliferation. Located in cytoplasm. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.11190755E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB5	NM_002639.5	c.559G>C	p.Val187Leu	missense_variant	Exon 5 of 7	ENST00000382771.9	NP_002630.2
SERPINB5	XM_006722483.4	c.46G>C	p.Val16Leu	missense_variant	Exon 2 of 4		XP_006722546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB5	ENST00000382771.9	c.559G>C	p.Val187Leu	missense_variant	Exon 5 of 7	1	NM_002639.5	ENSP00000372221.4
SERPINB5	ENST00000489441.5	c.559G>C	p.Val187Leu	missense_variant	Exon 5 of 5	1		ENSP00000467158.1
SERPINB5	ENST00000464346.1	n.241G>C		non_coding_transcript_exon_variant	Exon 2 of 4	3
SERPINB5	ENST00000465652.5	n.232G>C		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.222 AC: 33696 AN: 151994 Hom.: 7247 Cov.: 32

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0804

Gnomad EAS AF: 0.243

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.0294

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.0629

Gnomad OTH AF: 0.201

GnomAD2 exomes AF: 0.143 AC: 35901 AN: 251414 AF XY: 0.138

Gnomad AFR exome AF: 0.571

Gnomad AMR exome AF: 0.146

Gnomad ASJ exome AF: 0.0772

Gnomad EAS exome AF: 0.237

Gnomad FIN exome AF: 0.0299

Gnomad NFE exome AF: 0.0640

Gnomad OTH exome AF: 0.114

GnomAD4 exome AF: 0.0929 AC: 135835 AN: 1461668 Hom.: 13272 Cov.: 41 AF XY: 0.0963 AC XY: 70012 AN XY: 727126

African (AFR) AF: 0.577 AC: 19301 AN: 33464

American (AMR) AF: 0.147 AC: 6574 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0755 AC: 1973 AN: 26132

East Asian (EAS) AF: 0.229 AC: 9098 AN: 39698

South Asian (SAS) AF: 0.248 AC: 21356 AN: 86254

European-Finnish (FIN) AF: 0.0306 AC: 1633 AN: 53412

Middle Eastern (MID) AF: 0.194 AC: 1117 AN: 5764

European-Non Finnish (NFE) AF: 0.0603 AC: 67028 AN: 1111840

Other (OTH) AF: 0.128 AC: 7755 AN: 60380

GnomAD4 genome AF: 0.222 AC: 33783 AN: 152112 Hom.: 7286 Cov.: 32 AF XY: 0.220 AC XY: 16328 AN XY: 74364

African (AFR) AF: 0.557 AC: 23067 AN: 41420

American (AMR) AF: 0.172 AC: 2630 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0804 AC: 279 AN: 3470

East Asian (EAS) AF: 0.242 AC: 1254 AN: 5176

South Asian (SAS) AF: 0.266 AC: 1279 AN: 4816

European-Finnish (FIN) AF: 0.0294 AC: 312 AN: 10616

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.0629 AC: 4280 AN: 68008

Other (OTH) AF: 0.201 AC: 424 AN: 2112

Alfa AF: 0.0945 Hom.: 1126

Bravo AF: 0.244

TwinsUK AF: 0.0607 AC: 225

ALSPAC AF: 0.0607 AC: 234

ESP6500AA AF: 0.540 AC: 2380

ESP6500EA AF: 0.0656 AC: 564

ExAC AF: 0.151 AC: 18383

Asia WGS AF: 0.267 AC: 929 AN: 3478

EpiCase AF: 0.0736

EpiControl AF: 0.0801

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.80
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.79	T;T
MetaRNN	Benign	0.00011	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.17	N;N
PhyloP100		0.33
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.3	N;.
REVEL	Benign	0.033
Sift	Benign	0.94	T;.
Sift4G	Benign	0.79	T;T
Polyphen		0.0060	B;B
Vest4		0.089
MPC		0.059
ClinPred		0.0013	T
GERP RS		0.34
Varity_R		0.22
gMVP		0.65
Mutation Taster		=92/8	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2289520; hg19: chr18-61160320; COSMIC: COSV66975064; COSMIC: COSV66975064;