chr2-223991804-A-C

Variant names:

• chr2-223991804-A-C
• NM_001136528.2:c.684T>G

Variant summary

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

The NM_001136528.2(SERPINE2):​c.684T>G​(p.Cys228Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SERPINE2 NM_001136528.2 missense, splice_region
• Scores: Splicing: ADA: 0.0007382
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.520
• Publications: 0 publications found

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

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_001136528.2. 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
	SERPINE2	NM_001136528.2	MANE Select	c.684T>G	p.Cys228Trp	missense splice_region	Exon 4 of 9	NP_001130000.1	P07093-2
	SERPINE2	NM_001136530.1		c.720T>G	p.Cys240Trp	missense splice_region	Exon 4 of 9	NP_001130002.1	P07093-3
	SERPINE2	NM_006216.4		c.684T>G	p.Cys228Trp	missense splice_region	Exon 4 of 9	NP_006207.1	P07093-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINE2	ENST00000409304.6	TSL:1 MANE Select	c.684T>G	p.Cys228Trp	missense splice_region	Exon 4 of 9	ENSP00000386412.1	P07093-2
	SERPINE2	ENST00000258405.9	TSL:1	c.684T>G	p.Cys228Trp	missense splice_region	Exon 4 of 9	ENSP00000258405.4	P07093-1
	SERPINE2	ENST00000409840.7	TSL:1	c.684T>G	p.Cys228Trp	missense splice_region	Exon 5 of 10	ENSP00000386969.3	P07093-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	Benign	0.33
BayesDel_addAF	Benign	-0.0057	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.2	L
PhyloP100		-0.52
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.62	N
REVEL	Uncertain	0.42
Sift	Benign	0.19	T
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.42
MutPred		0.68		Gain of sheet (P = 0.0827)
MVP		0.62
MPC		1.1
ClinPred		0.72	D
GERP RS		-10
Varity_R		0.22
gMVP		0.89
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00074
dbscSNV1_RF	Benign	0.21
SpliceAI score (max)		0.050		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

hg19: chr2-224856521;