rs6103

Positions:

• chr18-63903269-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002575.3(SERPINB2):​c.1212C>G​(p.Asn404Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,548,660 control chromosomes in the GnomAD database, including 48,584 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.29 (6839 hom., cov: 33)
  • Exomes 𝑓: 0.24 (41745 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.33

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.1433946E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB2	NM_002575.3	c.1212C>G	p.Asn404Lys	missense_variant	8/8	ENST00000299502.9
SERPINB2	NM_001143818.2	c.1212C>G	p.Asn404Lys	missense_variant	9/9
SERPINB2	XM_024451192.2	c.1212C>G	p.Asn404Lys	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB2	ENST00000299502.9	c.1212C>G	p.Asn404Lys	missense_variant	8/8	1	NM_002575.3	P1
SERPINB2	ENST00000457692.5	c.1212C>G	p.Asn404Lys	missense_variant	9/9	5		P1

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43499 AN: 151956 Hom.: 6818 Cov.: 33

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.296

Gnomad FIN AF: 0.233

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.304

GnomAD3 exomes AF: 0.288 AC: 57714 AN: 200182 Hom.: 9211 AF XY: 0.281 AC XY: 30188 AN XY: 107398

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.437

Gnomad ASJ exome AF: 0.202

Gnomad EAS exome AF: 0.470

Gnomad SAS exome AF: 0.298

Gnomad FIN exome AF: 0.237

Gnomad NFE exome AF: 0.222

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.238 AC: 332050 AN: 1396586 Hom.: 41745 Cov.: 32 AF XY: 0.239 AC XY: 164519 AN XY: 689376

Gnomad4 AFR exome AF: 0.369

Gnomad4 AMR exome AF: 0.416

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.404

Gnomad4 SAS exome AF: 0.281

Gnomad4 FIN exome AF: 0.228

Gnomad4 NFE exome AF: 0.220

Gnomad4 OTH exome AF: 0.259

GnomAD4 genome AF: 0.286 AC: 43555 AN: 152074 Hom.: 6839 Cov.: 33 AF XY: 0.289 AC XY: 21515 AN XY: 74344

Gnomad4 AFR AF: 0.363

Gnomad4 AMR AF: 0.371

Gnomad4 ASJ AF: 0.184

Gnomad4 EAS AF: 0.478

Gnomad4 SAS AF: 0.296

Gnomad4 FIN AF: 0.233

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.310

Alfa AF: 0.239 Hom.: 1015

Bravo AF: 0.302

TwinsUK AF: 0.202 AC: 749

ALSPAC AF: 0.209 AC: 805

ESP6500AA AF: 0.369 AC: 1624

ESP6500EA AF: 0.218 AC: 1877

ExAC AF: 0.276 AC: 33421

Asia WGS AF: 0.394 AC: 1369 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.89	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.020
DANN	Benign	0.43
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
MetaRNN	Benign	0.00011	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.17	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.0080
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.041
MutPred		0.23		Gain of methylation at N404 (P = 2e-04);Gain of methylation at N404 (P = 2e-04);
MPC		0.016
ClinPred		0.0019	T
GERP RS		-2.4
Varity_R		0.17
gMVP		0.15

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: rs6103; hg19: chr18-61570503; COSMIC: COSV53073021; COSMIC: COSV53073021;