18-63493054-T-C

Variant names:

• chr18-63493054-T-C
• rs2289519
• NM_002639.5:c.526T>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.526T>C​(p.Ser176Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.687 in 1,613,908 control chromosomes in the GnomAD database, including 383,085 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.72 (40078 hom., cov: 32)
  • Exomes 𝑓: 0.68 (343007 hom.)
• Consequence: SERPINB5 NM_002639.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.00
• Publications: 40 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=6.527192E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.84 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB5	NM_002639.5	c.526T>C	p.Ser176Pro	missense_variant	Exon 5 of 7	ENST00000382771.9	NP_002630.2
SERPINB5	XM_006722483.4	c.13T>C	p.Ser5Pro	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.526T>C	p.Ser176Pro	missense_variant	Exon 5 of 7	1	NM_002639.5	ENSP00000372221.4
SERPINB5	ENST00000489441.5	c.526T>C	p.Ser176Pro	missense_variant	Exon 5 of 5	1		ENSP00000467158.1
SERPINB5	ENST00000464346.1	n.208T>C		non_coding_transcript_exon_variant	Exon 2 of 4	3
SERPINB5	ENST00000465652.5	n.199T>C		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109491 AN: 152024 Hom.: 40026 Cov.: 32

Gnomad AFR AF: 0.847

Gnomad AMI AF: 0.744

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.646

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.715

Gnomad NFE AF: 0.686

Gnomad OTH AF: 0.716

GnomAD2 exomes AF: 0.665 AC: 167203 AN: 251448 AF XY: 0.663

Gnomad AFR exome AF: 0.856

Gnomad AMR exome AF: 0.580

Gnomad ASJ exome AF: 0.651

Gnomad EAS exome AF: 0.607

Gnomad FIN exome AF: 0.633

Gnomad NFE exome AF: 0.688

Gnomad OTH exome AF: 0.676

GnomAD4 exome AF: 0.684 AC: 999344 AN: 1461766 Hom.: 343007 Cov.: 61 AF XY: 0.682 AC XY: 495785 AN XY: 727184

African (AFR) AF: 0.853 AC: 28569 AN: 33478

American (AMR) AF: 0.588 AC: 26293 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.648 AC: 16933 AN: 26136

East Asian (EAS) AF: 0.602 AC: 23913 AN: 39698

South Asian (SAS) AF: 0.632 AC: 54495 AN: 86240

European-Finnish (FIN) AF: 0.636 AC: 33992 AN: 53412

Middle Eastern (MID) AF: 0.714 AC: 4117 AN: 5768

European-Non Finnish (NFE) AF: 0.692 AC: 768947 AN: 1111918

Other (OTH) AF: 0.697 AC: 42085 AN: 60392

GnomAD4 genome AF: 0.720 AC: 109598 AN: 152142 Hom.: 40078 Cov.: 32 AF XY: 0.713 AC XY: 53043 AN XY: 74386

African (AFR) AF: 0.847 AC: 35164 AN: 41498

American (AMR) AF: 0.667 AC: 10198 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.646 AC: 2243 AN: 3472

East Asian (EAS) AF: 0.608 AC: 3142 AN: 5166

South Asian (SAS) AF: 0.640 AC: 3089 AN: 4824

European-Finnish (FIN) AF: 0.632 AC: 6691 AN: 10592

Middle Eastern (MID) AF: 0.735 AC: 216 AN: 294

European-Non Finnish (NFE) AF: 0.686 AC: 46655 AN: 67988

Other (OTH) AF: 0.721 AC: 1524 AN: 2114

Alfa AF: 0.701 Hom.: 102096

Bravo AF: 0.725

TwinsUK AF: 0.691 AC: 2562

ALSPAC AF: 0.692 AC: 2668

ESP6500AA AF: 0.841 AC: 3707

ESP6500EA AF: 0.690 AC: 5935

ExAC AF: 0.671 AC: 81503

Asia WGS AF: 0.675 AC: 2348 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Benign	0.90
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.077	T;T
MetaRNN	Benign	6.5e-7	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.83	N;N
PhyloP100		3.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.72	N;.
REVEL	Benign	0.23
Sift	Benign	0.50	T;.
Sift4G	Benign	0.40	T;T
Polyphen		0.0	B;B
Vest4		0.072
MPC		0.071
ClinPred		0.013	T
GERP RS		6.0
Varity_R		0.27
gMVP		0.84
Mutation Taster		=100/0	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: rs2289519; hg19: chr18-61160287; COSMIC: COSV66975060; COSMIC: COSV66975060;