rs6103

Variant names:

• chr18-63903269-C-G
• rs6103
• NM_002575.3:c.1212C>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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 0.29 (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
• Publications: 38 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.1212C>G	p.Asn404Lys	missense_variant	Exon 8 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.1212C>G	p.Asn404Lys	missense_variant	Exon 9 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.1212C>G	p.Asn404Lys	missense_variant	Exon 8 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.1212C>G	p.Asn404Lys	missense_variant	Exon 8 of 8	1	NM_002575.3	ENSP00000299502.4
ENSG00000289724	ENST00000418725.1	c.546+294C>G		intron_variant	Intron 5 of 6	5		ENSP00000392381.1
SERPINB2	ENST00000457692.5	c.1212C>G	p.Asn404Lys	missense_variant	Exon 9 of 9	5		ENSP00000401645.1
ENSG00000289724	ENST00000397996.6	c.546+294C>G		intron_variant	Intron 5 of 7	5		ENSP00000381082.2

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

GnomAD2 exomes AF: 0.288 AC: 57714 AN: 200182 AF XY: 0.281

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 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

African (AFR) AF: 0.369 AC: 11324 AN: 30650

American (AMR) AF: 0.416 AC: 13582 AN: 32664

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4156 AN: 22298

East Asian (EAS) AF: 0.404 AC: 15673 AN: 38788

South Asian (SAS) AF: 0.281 AC: 21491 AN: 76346

European-Finnish (FIN) AF: 0.228 AC: 11781 AN: 51570

Middle Eastern (MID) AF: 0.303 AC: 1648 AN: 5432

European-Non Finnish (NFE) AF: 0.220 AC: 237509 AN: 1081416

Other (OTH) AF: 0.259 AC: 14886 AN: 57422

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

African (AFR) AF: 0.363 AC: 15064 AN: 41474

American (AMR) AF: 0.371 AC: 5668 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3470

East Asian (EAS) AF: 0.478 AC: 2470 AN: 5162

South Asian (SAS) AF: 0.296 AC: 1427 AN: 4818

European-Finnish (FIN) AF: 0.233 AC: 2471 AN: 10588

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14947 AN: 67970

Other (OTH) AF: 0.310 AC: 653 AN: 2108

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
LIST_S2	Benign	0.018	.;T
MetaRNN	Benign	0.00011	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.17	N;N
PhyloP100		-1.3
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
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: rs6103; hg19: chr18-61570503; COSMIC: COSV53073021; COSMIC: COSV53073021;