chr18-63902411-G-A

Position:

• chr18-63902411-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000299502.9(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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (6 hom.)
• Consequence: SERPINB2 ENST00000299502.9 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.157

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 -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/exons	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.686G>A	p.Arg229His	missense_variant	7/8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.686G>A	p.Arg229His	missense_variant	8/9		NP_001137290.1
SERPINB2	XM_024451192.2	c.686G>A	p.Arg229His	missense_variant	7/8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.686G>A	p.Arg229His	missense_variant	7/8	1	NM_002575.3	ENSP00000299502	P1
SERPINB2	ENST00000457692.5	c.686G>A	p.Arg229His	missense_variant	8/9	5		ENSP00000401645	P1
SERPINB2	ENST00000482254.1	n.642G>A		non_coding_transcript_exon_variant	6/6	5

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

GnomAD3 exomes AF: 0.00143 AC: 344 AN: 240504 Hom.: 1 AF XY: 0.00137 AC XY: 178 AN XY: 130144

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 SAS 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

Gnomad4 AFR exome AF: 0.000825

Gnomad4 AMR exome AF: 0.000736

Gnomad4 ASJ exome AF: 0.000118

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00347

Gnomad4 NFE exome AF: 0.00163

Gnomad4 OTH exome AF: 0.000989

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

Gnomad4 AFR AF: 0.000795

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00340

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00280 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

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2019	- -

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
MutationTaster	Benign	1.0	N;N
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

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