chr2-223977558-C-A

Variant names:

• chr2-223977558-C-A
• NM_001136528.2:c.1142G>T

Variant summary

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

The NM_001136528.2(SERPINE2):​c.1142G>T​(p.Arg381Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R381Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SERPINE2 NM_001136528.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.28

Genes affected

SERPINE2 (HGNC:8951): (serpin family E member 2) This gene encodes a member of the serpin family of proteins, a group of proteins that inhibit serine proteases. Thrombin, urokinase, plasmin and trypsin are among the proteases that this family member can inhibit. This gene is a susceptibility gene for chronic obstructive pulmonary disease and for emphysema. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

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, 0.926

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINE2	NM_001136528.2	c.1142G>T	p.Arg381Leu	missense_variant	Exon 8 of 9	ENST00000409304.6	NP_001130000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINE2	ENST00000409304.6	c.1142G>T	p.Arg381Leu	missense_variant	Exon 8 of 9	1	NM_001136528.2	ENSP00000386412.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456498 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725012

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	.;D;.;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.93	D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.9	.;M;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.8	D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.027	D;D;D;D
Polyphen		1.0	.;D;.;.
Vest4		0.91
MutPred		0.77		.;Gain of catalytic residue at F379 (P = 0.2801);.;.;
MVP		0.94
MPC		1.2
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.80
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-224842275;