3-167452954-C-T

Variant names:

• chr3-167452954-C-T
• rs552142791
• NM_006217.6:c.946G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006217.6(SERPINI2):​c.946G>A​(p.Asp316Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,598,512 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: SERPINI2 NM_006217.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.98

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18774474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINI2	NM_006217.6	c.946G>A	p.Asp316Asn	missense_variant	Exon 6 of 9	ENST00000264677.9	NP_006208.1
SERPINI2	NM_001012303.3	c.946G>A	p.Asp316Asn	missense_variant	Exon 7 of 10		NP_001012303.2
SERPINI2	NM_001394327.1	c.946G>A	p.Asp316Asn	missense_variant	Exon 7 of 10		NP_001381256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINI2	ENST00000264677.9	c.946G>A	p.Asp316Asn	missense_variant	Exon 6 of 9	1	NM_006217.6	ENSP00000264677.4
SERPINI2	ENST00000461846.5	c.946G>A	p.Asp316Asn	missense_variant	Exon 6 of 9	1		ENSP00000417692.1
SERPINI2	ENST00000471111.5	c.946G>A	p.Asp316Asn	missense_variant	Exon 5 of 8	1		ENSP00000419407.1

Frequencies

GnomAD3 genomes AF: 0.0000528 AC: 8 AN: 151614 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.0000247 AC: 6 AN: 243098 Hom.: 0 AF XY: 0.0000381 AC XY: 5 AN XY: 131256

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000338

Gnomad SAS 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: 0.0000131 AC: 19 AN: 1446780 Hom.: 0 Cov.: 27 AF XY: 0.00000695 AC XY: 5 AN XY: 719762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000231

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000507

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000997

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000527 AC: 8 AN: 151732 Hom.: 0 Cov.: 32 AF XY: 0.0000540 AC XY: 4 AN XY: 74130

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.0000831

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 18, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.946G>A (p.D316N) alteration is located in exon 6 (coding exon 5) of the SERPINI2 gene. This alteration results from a G to A substitution at nucleotide position 946, causing the aspartic acid (D) at amino acid position 316 to be replaced by an asparagine (N). 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	0.13
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T;T;T;T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.75	T;T;.;.;.
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.19	T;T;T;T;T
MetaSVM	Uncertain	0.051	D
MutationAssessor	Benign	1.5	L;.;L;L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.6	D;.;D;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.30	T;.;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T
Polyphen		1.0	D;.;D;D;D
Vest4		0.29
MVP		0.65
MPC		0.30
ClinPred		0.34	T
GERP RS		3.7
Varity_R		0.31
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs552142791; hg19: chr3-167170742; COSMIC: COSV52985273;