chr18-63903295-C-G

Variant names:

• chr18-63903295-C-G
• rs6104
• NM_002575.3:c.1238C>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.1238C>G​(p.Ser413Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 1,526,154 control chromosomes in the GnomAD database, including 47,860 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 (6832 hom., cov: 32)
  • Exomes 𝑓: 0.24 (41028 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.933
• Publications: 46 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=3.8471818E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.1238C>G	p.Ser413Cys	missense_variant	Exon 8 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.1238C>G	p.Ser413Cys	missense_variant	Exon 9 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.1238C>G	p.Ser413Cys	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.1238C>G	p.Ser413Cys	missense_variant	Exon 8 of 8	1	NM_002575.3	ENSP00000299502.4
ENSG00000289724	ENST00000418725.1	c.546+320C>G		intron_variant	Intron 5 of 6	5		ENSP00000392381.1
SERPINB2	ENST00000457692.5	c.1238C>G	p.Ser413Cys	missense_variant	Exon 9 of 9	5		ENSP00000401645.1
ENSG00000289724	ENST00000397996.6	c.546+320C>G		intron_variant	Intron 5 of 7	5		ENSP00000381082.2

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43471 AN: 151878 Hom.: 6811 Cov.: 32

Gnomad AFR AF: 0.363

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.370

Gnomad ASJ AF: 0.184

Gnomad EAS AF: 0.478

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: 0.289 AC: 53535 AN: 185116 AF XY: 0.282

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.435

Gnomad ASJ exome AF: 0.200

Gnomad EAS exome AF: 0.470

Gnomad FIN exome AF: 0.235

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.277

GnomAD4 exome AF: 0.237 AC: 326206 AN: 1374158 Hom.: 41028 Cov.: 32 AF XY: 0.238 AC XY: 160668 AN XY: 674504

African (AFR) AF: 0.369 AC: 11244 AN: 30466

American (AMR) AF: 0.416 AC: 13203 AN: 31704

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 3882 AN: 20828

East Asian (EAS) AF: 0.404 AC: 15580 AN: 38564

South Asian (SAS) AF: 0.281 AC: 20100 AN: 71460

European-Finnish (FIN) AF: 0.228 AC: 11538 AN: 50582

Middle Eastern (MID) AF: 0.305 AC: 1625 AN: 5334

European-Non Finnish (NFE) AF: 0.219 AC: 234375 AN: 1068600

Other (OTH) AF: 0.259 AC: 14659 AN: 56620

GnomAD4 genome AF: 0.286 AC: 43527 AN: 151996 Hom.: 6832 Cov.: 32 AF XY: 0.289 AC XY: 21504 AN XY: 74282

African (AFR) AF: 0.363 AC: 15061 AN: 41448

American (AMR) AF: 0.371 AC: 5657 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.184 AC: 638 AN: 3468

East Asian (EAS) AF: 0.477 AC: 2456 AN: 5146

South Asian (SAS) AF: 0.296 AC: 1426 AN: 4814

European-Finnish (FIN) AF: 0.233 AC: 2469 AN: 10574

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

European-Non Finnish (NFE) AF: 0.220 AC: 14951 AN: 67968

Other (OTH) AF: 0.310 AC: 652 AN: 2104

Alfa AF: 0.216 Hom.: 2480

Bravo AF: 0.302

TwinsUK AF: 0.202 AC: 749

ALSPAC AF: 0.209 AC: 804

ESP6500AA AF: 0.369 AC: 1624

ESP6500EA AF: 0.217 AC: 1869

ExAC AF: 0.273 AC: 32773

Asia WGS AF: 0.389 AC: 1349 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	1.5
DANN	Benign	0.44
DEOGEN2	Benign	0.12	T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.81	.;T
MetaRNN	Benign	0.00038	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.61	N;N
PhyloP100		0.93
PrimateAI	Benign	0.26	T
PROVEAN	Benign	3.3	N;N
REVEL	Benign	0.12
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0030	B;B
Vest4		0.065
MPC		0.016
ClinPred		0.00070	T
GERP RS		1.3
Varity_R		0.19
gMVP		0.19
Mutation Taster		=98/2	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: rs6104; hg19: chr18-61570529; COSMIC: COSV53073025; COSMIC: COSV53073025;