Genetic Variant NM_002575.3:c.124G>T (chr18-63891568-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_002575.3(SERPINB2):c.124G>T(p.Val42Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V42I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SERPINB2
NM_002575.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.02

Publications

0 publications found

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:

LOC124904356 (HGNC:):

LOC124904356 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3 link	c.124G>T	p.Val42Phe	missense_variant	Exon 2 of 8	ENST00000299502.9	NP_002566.1	P05120
SERPINB2	NM_001143818.2 link	c.124G>T	p.Val42Phe	missense_variant	Exon 3 of 9		NP_001137290.1	P05120
SERPINB2	XM_024451192.2 link	c.124G>T	p.Val42Phe	missense_variant	Exon 2 of 8		XP_024306960.1
LOC124904356	XR_007066466.1 link	n.183+1053C>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9 link	c.124G>T	p.Val42Phe	missense_variant	Exon 2 of 8	1	NM_002575.3	ENSP00000299502.4		P05120

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461818

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.36

T;T;T;T;T

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.92

D;.;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.90

D;D;D;D;D

MetaSVM

Uncertain

0.27

MutationAssessor

Pathogenic

3.4

.;M;M;.;.

PhyloP100

2.0

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-4.5

D;D;D;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D;D

Polyphen

0.95

.;P;P;.;.

Vest4

0.83, 0.83

MutPred

0.80

Loss of glycosylation at S46 (P = 0.0884);Loss of glycosylation at S46 (P = 0.0884);Loss of glycosylation at S46 (P = 0.0884);Loss of glycosylation at S46 (P = 0.0884);Loss of glycosylation at S46 (P = 0.0884);

MVP

0.75

MPC

0.12

ClinPred

0.98

GERP RS

0.54

Varity_R

0.87

gMVP

0.69

Mutation Taster

=25/75

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over