18-63901749-C-A

Variant names:

• chr18-63901749-C-A
• rs2049992171
• NM_002575.3:c.545C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002575.3(SERPINB2):​c.545C>A​(p.Pro182Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,393,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P182L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43

Genes affected

SERPINB2 (HGNC:8584): (serpin family B member 2) Predicted to enable serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be located in extracellular region and plasma membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000289724 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23684457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.545C>A	p.Pro182Gln	missense_variant	Exon 6 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.545C>A	p.Pro182Gln	missense_variant	Exon 7 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.545C>A	p.Pro182Gln	missense_variant	Exon 6 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.545C>A	p.Pro182Gln	missense_variant	Exon 6 of 8	1	NM_002575.3	ENSP00000299502.4
ENSG00000289724	ENST00000397996.6	c.173C>A	p.Pro58Gln	missense_variant	Exon 3 of 8	5		ENSP00000381082.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1393758 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 691310

Gnomad4 AFR exome AF: 0.0000346

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.545C>A (p.P182Q) alteration is located in exon 7 (coding exon 5) of the SERPINB2 gene. This alteration results from a C to A substitution at nucleotide position 545, causing the proline (P) at amino acid position 182 to be replaced by a glutamine (Q). 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	0.10
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	8.0
DANN	Benign	0.83
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.21	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.83	N;N
REVEL	Uncertain	0.31
Sift	Benign	0.48	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.94	P;P
Vest4		0.24
MutPred		0.39		Gain of MoRF binding (P = 0.0538);Gain of MoRF binding (P = 0.0538);
MVP		0.47
MPC		0.018
ClinPred		0.44	T
GERP RS		4.1
Varity_R		0.10
gMVP		0.27

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: rs2049992171; hg19: chr18-61568983;