2-223991804-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 15/23 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

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 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINE2	NM_001136528.2	c.684T>G	p.Cys228Trp	missense_variant, splice_region_variant	Exon 4 of 9	ENST00000409304.6	NP_001130000.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINE2	ENST00000409304.6	c.684T>G	p.Cys228Trp	missense_variant, splice_region_variant	Exon 4 of 9	1	NM_001136528.2	ENSP00000386412.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.720T>G (p.C240W) alteration is located in exon 4 (coding exon 4) of the SERPINE2 gene. This alteration results from a T to G substitution at nucleotide position 720, causing the cysteine (C) at amino acid position 240 to be replaced by a tryptophan (W). 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	0.33
BayesDel_addAF	Benign	-0.0057	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	12
DANN	Benign	0.97
DEOGEN2	Benign	0.39	.;T;.;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.80	.;T;T;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.43	T;T;T;T;T
MetaSVM	Uncertain	0.20	D
MutationAssessor	Benign	1.2	L;L;L;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.62	N;N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.19	T;T;T;T;T
Sift4G	Benign	0.18	T;T;T;T;.
Polyphen		0.99	.;D;.;.;.
Vest4		0.42
MutPred		0.68		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-224856521;