Genetic Variant NM_006217.6:c.980A>G (chr3-167449387-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006217.6(SERPINI2):c.980A>G(p.Tyr327Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y327F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SERPINI2
NM_006217.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.18

Variant links:

Genes affected

SERPINI2 (HGNC:8945): (serpin family I member 2) The gene encodes a member of a family of proteins that acts as inhibitors of serine proteases. These proteins function in the regulation of a variety of physiological processes, including coagulation, fibrinolysis, development, malignancy, and inflammation. Expression of the encoded protein may be downregulated during pancreatic carcinogenesis. Alternative splicing results in multiple transcript variants for this gene. [provided by RefSeq, Jan 2013]

SERPINI2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI2	NM_006217.6 link	c.980A>G	p.Tyr327Cys	missense_variant	Exon 7 of 9	ENST00000264677.9	NP_006208.1	O75830B4DDY9
SERPINI2	NM_001012303.3 link	c.980A>G	p.Tyr327Cys	missense_variant	Exon 8 of 10		NP_001012303.2	O75830B4DDY9
SERPINI2	NM_001394327.1 link	c.980A>G	p.Tyr327Cys	missense_variant	Exon 8 of 10		NP_001381256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SERPINI2	ENST00000264677.9 link	c.980A>G	p.Tyr327Cys	missense_variant	Exon 7 of 9	1	NM_006217.6	ENSP00000264677.4	O75830
SERPINI2	ENST00000461846.5 link	c.980A>G	p.Tyr327Cys	missense_variant	Exon 7 of 9	1		ENSP00000417692.1	O75830
SERPINI2	ENST00000471111.5 link	c.980A>G	p.Tyr327Cys	missense_variant	Exon 6 of 8	1		ENSP00000419407.1	O75830

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

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

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41442

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.021

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

D;T;D;D;D

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.80

T;T;.;.;.

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.58

D;D;D;D;D

MetaSVM

Uncertain

-0.045

MutationAssessor

Benign

1.3

L;.;L;L;L

PhyloP100

3.2

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-4.2

D;.;D;D;D

REVEL

Uncertain

0.53

Sift

Uncertain

0.0050

D;.;D;D;D

Sift4G

Uncertain

0.018

D;D;D;D;D

Polyphen

0.99

D;.;D;D;D

Vest4

0.49

MutPred

0.55

Gain of glycosylation at Y327 (P = 0.032);.;Gain of glycosylation at Y327 (P = 0.032);Gain of glycosylation at Y327 (P = 0.032);Gain of glycosylation at Y327 (P = 0.032);

MVP

0.39

MPC

0.73

ClinPred

0.99

GERP RS

4.5

Varity_R

0.35

gMVP

0.54

Mutation Taster

=88/12

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over