Genetic Variant NM_002575.3:c.220G>C (chr18-63895315-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002575.3(SERPINB2):c.220G>C(p.Glu74Gln) 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 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. E74K) 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: -0.112

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09098038).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB2	NM_002575.3 link	c.220G>C	p.Glu74Gln	missense_variant	Exon 3 of 8	ENST00000299502.9	NP_002566.1	P05120
SERPINB2	NM_001143818.2 link	c.220G>C	p.Glu74Gln	missense_variant	Exon 4 of 9		NP_001137290.1	P05120
SERPINB2	XM_024451192.2 link	c.220G>C	p.Glu74Gln	missense_variant	Exon 3 of 8		XP_024306960.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB2	ENST00000299502.9 link	c.220G>C	p.Glu74Gln	missense_variant	Exon 3 of 8	1	NM_002575.3	ENSP00000299502.4		P05120

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461812

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111966

Other (OTH)

AF:

0.00

AC:

AN:

60390

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

Benign

0.084

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

0.33

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.093

T;T;T;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.033

LIST_S2

Benign

0.55

T;.;T;T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.091

T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

0.38

.;N;N;.;.

PhyloP100

-0.11

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.040

N;N;N;N;N

REVEL

Benign

0.21

Sift

Benign

0.19

T;T;T;T;T

Sift4G

Benign

0.15

T;T;T;T;T

Polyphen

0.0050

.;B;B;.;.

Vest4

0.073, 0.064

MutPred

0.32

Loss of glycosylation at P73 (P = 0.1104);Loss of glycosylation at P73 (P = 0.1104);Loss of glycosylation at P73 (P = 0.1104);Loss of glycosylation at P73 (P = 0.1104);Loss of glycosylation at P73 (P = 0.1104);

MVP

0.62

MPC

0.016

ClinPred

0.12

GERP RS

-5.1

Varity_R

0.094

gMVP

0.18

Mutation Taster

=99/1

polymorphism

(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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NM_002575.3:c.220G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over