Genetic Variant NM_002575.3:c.124G>A (chr18-63891568-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002575.3(SERPINB2):c.124G>A(p.Val42Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

SERPINB2
NM_002575.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.02

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29205877).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3 link	c.124G>A	p.Val42Ile	missense_variant	Exon 2 of 8	ENST00000299502.9	NP_002566.1	P05120
SERPINB2	NM_001143818.2 link	c.124G>A	p.Val42Ile	missense_variant	Exon 3 of 9		NP_001137290.1	P05120
SERPINB2	XM_024451192.2 link	c.124G>A	p.Val42Ile	missense_variant	Exon 2 of 8		XP_024306960.1
LOC124904356	XR_007066466.1 link	n.183+1053C>T		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>A	p.Val42Ile	missense_variant	Exon 2 of 8	1	NM_002575.3	ENSP00000299502.4		P05120

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.124G>A (p.V42I) alteration is located in exon 3 (coding exon 1) of the SERPINB2 gene. This alteration results from a G to A substitution at nucleotide position 124, causing the valine (V) at amino acid position 42 to be replaced by an isoleucine (I). 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

0.091

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.10

T;T;T;T;T

Eigen

Benign

-0.41

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.79

T;.;T;T;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.29

T;T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Benign

1.6

.;L;L;.;.

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.67

N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

0.072

T;T;T;D;T

Sift4G

Benign

0.18

T;T;T;T;T

Polyphen

0.015

.;B;B;.;.

Vest4

0.18, 0.19

MutPred

0.56

Loss of glycosylation at S46 (P = 0.1202);Loss of glycosylation at S46 (P = 0.1202);Loss of glycosylation at S46 (P = 0.1202);Loss of glycosylation at S46 (P = 0.1202);Loss of glycosylation at S46 (P = 0.1202);

MVP

0.55

MPC

0.019

ClinPred

0.12

GERP RS

0.54

Varity_R

0.30

gMVP

0.18

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over