chr18-63901872-G-A

Variant names:

• chr18-63901872-G-A
• rs184826316
• NM_002575.3:c.668G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002575.3(SERPINB2):​c.668G>A​(p.Arg223His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,598,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: SERPINB2 NM_002575.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.247
• Publications: 3 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.091499984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3	c.668G>A	p.Arg223His	missense_variant	Exon 6 of 8	ENST00000299502.9	NP_002566.1
SERPINB2	NM_001143818.2	c.668G>A	p.Arg223His	missense_variant	Exon 7 of 9		NP_001137290.1
SERPINB2	XM_024451192.2	c.668G>A	p.Arg223His	missense_variant	Exon 6 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9	c.668G>A	p.Arg223His	missense_variant	Exon 6 of 8	1	NM_002575.3	ENSP00000299502.4
ENSG00000289724	ENST00000418725.1	c.296G>A	p.Arg99His	missense_variant	Exon 3 of 7	5		ENSP00000392381.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000132 AC: 31 AN: 234808 AF XY: 0.000133

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000169

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.000177

GnomAD4 exome AF: 0.000123 AC: 178 AN: 1445860 Hom.: 0 Cov.: 30 AF XY: 0.000132 AC XY: 95 AN XY: 718964

African (AFR) AF: 0.0000309 AC: 1 AN: 32316

American (AMR) AF: 0.000174 AC: 7 AN: 40230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25748

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38806

South Asian (SAS) AF: 0.000242 AC: 20 AN: 82572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5726

European-Non Finnish (NFE) AF: 0.000132 AC: 146 AN: 1107424

Other (OTH) AF: 0.0000502 AC: 3 AN: 59744

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74450

African (AFR) AF: 0.000120 AC: 5 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000976 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000140 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.668G>A (p.R223H) alteration is located in exon 7 (coding exon 5) of the SERPINB2 gene. This alteration results from a G to A substitution at nucleotide position 668, causing the arginine (R) at amino acid position 223 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.091	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.46	N;N
PhyloP100		0.25
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Benign	0.045
Sift	Uncertain	0.025	D;D
Sift4G	Uncertain	0.033	D;D
Polyphen		0.037	B;B
Vest4		0.25
MVP		0.040
MPC		0.018
ClinPred		0.072	T
GERP RS		2.0
Varity_R		0.41
gMVP		0.35
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs184826316; hg19: chr18-61569106; COSMIC: COSV55092540; COSMIC: COSV55092540;