18-63902411-G-A

Variant names:

• chr18-63902411-G-A
• rs6100
• NM_002575.3:c.686G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002575.3(SERPINB2):​c.686G>A​(p.Arg229His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,597,266 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.157
• Publications: 27 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041959584).
• BP6: Variant 18-63902411-G-A is Benign according to our data. Variant chr18-63902411-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 728330.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.686G>A	p.Arg229His	missense_variant	Exon 7 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.686G>A	p.Arg229His	missense_variant	Exon 8 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.686G>A	p.Arg229His	missense_variant	Exon 7 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.686G>A	p.Arg229His	missense_variant	Exon 7 of 8	1	NM_002575.3	ENSP00000299502.4
ENSG00000289724	ENST00000418725.1	c.314G>A	p.Arg105His	missense_variant	Exon 4 of 7	5		ENSP00000392381.1

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 299 AN: 152040 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00340

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00143 AC: 344 AN: 240504 AF XY: 0.00137

Gnomad AFR exome AF: 0.000760

Gnomad AMR exome AF: 0.000378

Gnomad ASJ exome AF: 0.000208

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00276

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00138

GnomAD4 exome AF: 0.00146 AC: 2104 AN: 1445108 Hom.: 6 Cov.: 31 AF XY: 0.00152 AC XY: 1094 AN XY: 718106

African (AFR) AF: 0.000825 AC: 27 AN: 32716

American (AMR) AF: 0.000736 AC: 31 AN: 42148

Ashkenazi Jewish (ASJ) AF: 0.000118 AC: 3 AN: 25508

East Asian (EAS) AF: 0.00 AC: 0 AN: 39312

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83418

European-Finnish (FIN) AF: 0.00347 AC: 184 AN: 53058

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5692

European-Non Finnish (NFE) AF: 0.00163 AC: 1797 AN: 1103610

Other (OTH) AF: 0.000989 AC: 59 AN: 59646

GnomAD4 genome AF: 0.00197 AC: 299 AN: 152158 Hom.: 1 Cov.: 33 AF XY: 0.00183 AC XY: 136 AN XY: 74374

African (AFR) AF: 0.000795 AC: 33 AN: 41534

American (AMR) AF: 0.000524 AC: 8 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00340 AC: 36 AN: 10578

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00325 AC: 221 AN: 68002

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.00263 Hom.: 4

Bravo AF: 0.00129

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00137 AC: 166

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 02, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	7.6
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.066	N
LIST_S2	Benign	0.27	.;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0042	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.58	N;N
PhyloP100		-0.16
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.0	N;N
REVEL	Benign	0.082
Sift	Benign	0.20	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.038	B;B
Vest4		0.043
MVP		0.44
MPC		0.016
ClinPred		0.0026	T
GERP RS		1.2
Varity_R		0.058
gMVP		0.24
Mutation Taster		=96/4	polymorphism

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: rs6100; hg19: chr18-61569645; COSMIC: COSV55094393; COSMIC: COSV55094393;