18-63493075-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002639.5(SERPINB5):c.547T>C(p.Cys183Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000617 in 1,614,178 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (0 hom.)
• Consequence: SERPINB5 NM_002639.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.02

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.030227125).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB5	NM_002639.5	c.547T>C	p.Cys183Arg	missense_variant	5/7	ENST00000382771.9
SERPINB5	XM_006722483.4	c.34T>C	p.Cys12Arg	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB5	ENST00000382771.9	c.547T>C	p.Cys183Arg	missense_variant	5/7	1	NM_002639.5	P1
SERPINB5	ENST00000489441.5	c.547T>C	p.Cys183Arg	missense_variant	5/5	1
SERPINB5	ENST00000464346.1	n.229T>C		non_coding_transcript_exon_variant	2/4	3
SERPINB5	ENST00000465652.5	n.220T>C		non_coding_transcript_exon_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000529 AC: 133 AN: 251446 Hom.: 0 AF XY: 0.000537 AC XY: 73 AN XY: 135906

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000800

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000633 AC: 926 AN: 1461864 Hom.: 0 Cov.: 41 AF XY: 0.000659 AC XY: 479 AN XY: 727232

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.000683

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152314 Hom.: 0 Cov.: 33 AF XY: 0.000483 AC XY: 36 AN XY: 74494

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000794

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000862 Hom.: 0

Bravo AF: 0.000578

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000576 AC: 70

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00184

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.547T>C (p.C183R) alteration is located in exon 5 (coding exon 4) of the SERPINB5 gene. This alteration results from a T to C substitution at nucleotide position 547, causing the cysteine (C) at amino acid position 183 to be replaced by an arginine (R). 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	0.17
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	16
Dann	Benign	0.82
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.030	T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.95	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.21
Sift	Benign	0.51	T;.
Sift4G	Benign	0.56	T;D
Polyphen		0.0040	B;B
Vest4		0.29
MVP		0.65
MPC		0.10
ClinPred		0.0098	T
GERP RS		3.7
Varity_R		0.32
gMVP		0.84

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: rs140393612; hg19: chr18-61160308;