3-167465287-A-C

Variant names:

• chr3-167465287-A-C
• rs1750100634
• NM_006217.6:c.785T>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_006217.6(SERPINI2):​c.785T>G​(p.Val262Gly) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SERPINI2 NM_006217.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI2	NM_006217.6	c.785T>G	p.Val262Gly	missense_variant	Exon 5 of 9	ENST00000264677.9	NP_006208.1
SERPINI2	NM_001012303.3	c.785T>G	p.Val262Gly	missense_variant	Exon 6 of 10		NP_001012303.2
SERPINI2	NM_001394327.1	c.785T>G	p.Val262Gly	missense_variant	Exon 6 of 10		NP_001381256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI2	ENST00000264677.9	c.785T>G	p.Val262Gly	missense_variant	Exon 5 of 9	1	NM_006217.6	ENSP00000264677.4
SERPINI2	ENST00000461846.5	c.785T>G	p.Val262Gly	missense_variant	Exon 5 of 9	1		ENSP00000417692.1
SERPINI2	ENST00000471111.5	c.785T>G	p.Val262Gly	missense_variant	Exon 4 of 8	1		ENSP00000419407.1
SERPINI2	ENST00000466903.1	c.*247T>G		downstream_gene_variant		3		ENSP00000417752.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.785T>G (p.V262G) alteration is located in exon 5 (coding exon 4) of the SERPINI2 gene. This alteration results from a T to G substitution at nucleotide position 785, causing the valine (V) at amino acid position 262 to be replaced by a glycine (G). 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	0.28
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;T;D;D;D
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.47	T;T;.;.;.
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D
MetaSVM	Uncertain	0.048	D
MutationAssessor	Pathogenic	3.0	M;.;M;M;M
PrimateAI	Benign	0.29	T
PROVEAN	Pathogenic	-5.5	D;.;D;D;D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0020	D;.;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D
Polyphen		0.38	B;.;B;B;B
Vest4		0.50
MutPred		0.83		Gain of disorder (P = 0.0073);.;Gain of disorder (P = 0.0073);Gain of disorder (P = 0.0073);Gain of disorder (P = 0.0073);
MVP		0.74
MPC		0.46
ClinPred		0.98	D
GERP RS		3.4
Varity_R		0.69
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1750100634; hg19: chr3-167183075;