3-167452980-A-G

Variant names:

• chr3-167452980-A-G
• rs369145054
• NM_006217.6:c.920T>C

Variant summary

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

The NM_006217.6(SERPINI2):​c.920T>C​(p.Ile307Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000106 in 1,608,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I307V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: SERPINI2 NM_006217.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.26
• Publications: 0 publications found

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]

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006217.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINI2	NM_006217.6	MANE Select	c.920T>C	p.Ile307Thr	missense	Exon 6 of 9	NP_006208.1	O75830
	SERPINI2	NM_001012303.3		c.920T>C	p.Ile307Thr	missense	Exon 7 of 10	NP_001012303.2	O75830
	SERPINI2	NM_001394327.1		c.920T>C	p.Ile307Thr	missense	Exon 7 of 10	NP_001381256.1	O75830

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINI2	ENST00000264677.9	TSL:1 MANE Select	c.920T>C	p.Ile307Thr	missense	Exon 6 of 9	ENSP00000264677.4	O75830
	SERPINI2	ENST00000461846.5	TSL:1	c.920T>C	p.Ile307Thr	missense	Exon 6 of 9	ENSP00000417692.1	O75830
	SERPINI2	ENST00000471111.5	TSL:1	c.920T>C	p.Ile307Thr	missense	Exon 5 of 8	ENSP00000419407.1	O75830

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000478

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248268 AF XY: 0.0000149

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000550 AC: 8 AN: 1455782 Hom.: 0 Cov.: 28 AF XY: 0.00000552 AC XY: 4 AN XY: 724234

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000904 AC: 3 AN: 33196

American (AMR) AF: 0.0000226 AC: 1 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25962

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 85034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53338

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108618

Other (OTH) AF: 0.0000665 AC: 4 AN: 60142

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000242037), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74446

African (AFR) AF: 0.000144 AC: 6 AN: 41574

American (AMR) AF: 0.000131 AC: 2 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000907

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.089	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		5.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.32	B
Vest4		0.68
MVP		0.72
MPC		0.50
ClinPred		0.82	D
GERP RS		5.5
Varity_R		0.48
gMVP		0.83
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs369145054; hg19: chr3-167170768;