Variant 18-63901869-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002575.3(SERPINB2):c.665T>C(p.Phe222Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000113 in 1,599,768 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

SERPINB2
NM_002575.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.13

Variant links:

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]

SERPINB2 links:

ENSG00000289724 (HGNC:):

ENSG00000289724 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SERPINB2	NM_002575.3 linkuse as main transcript	c.665T>C	p.Phe222Ser	missense_variant	6/8	ENST00000299502.9	NP_002566.1	P05120
SERPINB2	NM_001143818.2 linkuse as main transcript	c.665T>C	p.Phe222Ser	missense_variant	7/9		NP_001137290.1	P05120
SERPINB2	XM_024451192.2 linkuse as main transcript	c.665T>C	p.Phe222Ser	missense_variant	6/8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9 linkuse as main transcript	c.665T>C	p.Phe222Ser	missense_variant	6/8	1	NM_002575.3	ENSP00000299502.4		P05120
ENSG00000289724	ENST00000397996.6 linkuse as main transcript	c.293T>C	p.Phe98Ser	missense_variant	3/8	5		ENSP00000381082.2		H7BYS2

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000241

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

236490

Hom.:

AF XY:

0.00000780

AC XY:

AN XY:

128192

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000553

AC:

AN:

1447564

Hom.:

Cov.:

AF XY:

0.00000695

AC XY:

AN XY:

719836

show subpopulations

Gnomad4 AFR exome

AF:

0.000216

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.02e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000529

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2024

The c.665T>C (p.F222S) alteration is located in exon 7 (coding exon 5) of the SERPINB2 gene. This alteration results from a T to C substitution at nucleotide position 665, causing the phenylalanine (F) at amino acid position 222 to be replaced by a serine (S). 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

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.71

.;T

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;H

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-7.7

D;D

REVEL

Pathogenic

0.98

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.98

MutPred

0.92

Gain of disorder (P = 0.0032);Gain of disorder (P = 0.0032);

MVP

0.88

MPC

0.13

ClinPred

1.0

GERP RS

5.8

Varity_R

0.99

gMVP

0.90

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over