18-63897124-C-T

Variant names:

• chr18-63897124-C-T
• rs774883619
• NM_002575.3:c.322C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002575.3(SERPINB2):​c.322C>T​(p.Arg108Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.997
• Publications: 3 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.322C>T	p.Arg108Cys	missense_variant	Exon 4 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.322C>T	p.Arg108Cys	missense_variant	Exon 5 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.322C>T	p.Arg108Cys	missense_variant	Exon 4 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.322C>T	p.Arg108Cys	missense_variant	Exon 4 of 8	1	NM_002575.3	ENSP00000299502.4
ENSG00000289724	ENST00000418725.1	c.-51C>T		upstream_gene_variant		5		ENSP00000392381.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250676 AF XY: 0.0000148

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1460842 Hom.: 0 Cov.: 30 AF XY: 0.0000619 AC XY: 45 AN XY: 726676

African (AFR) AF: 0.000179 AC: 6 AN: 33444

American (AMR) AF: 0.0000224 AC: 1 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 86158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000783 AC: 87 AN: 1111368

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74324

African (AFR) AF: 0.000121 AC: 5 AN: 41426

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000793

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.322C>T (p.R108C) alteration is located in exon 5 (coding exon 3) of the SERPINB2 gene. This alteration results from a C to T substitution at nucleotide position 322, causing the arginine (R) at amino acid position 108 to be replaced by a cysteine (C). 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	0.076
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;D;D;T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.61	T;.;T;T;T
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.50	T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Uncertain	2.1	.;M;M;.;.
PhyloP100		-1.0
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Uncertain	0.41
Sift	Benign	0.059	T;D;D;T;D
Sift4G	Benign	0.083	T;D;D;D;T
Polyphen		1.0	.;D;D;.;.
Vest4		0.092, 0.097
MutPred		0.69		Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);Loss of disorder (P = 0.0345);
MVP		0.83
MPC		0.017
ClinPred		0.40	T
GERP RS		0.073
PromoterAI		-0.0015	Neutral
Varity_R		0.34
gMVP		0.25
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs774883619; hg19: chr18-61564358;