2-232379275-C-G

Position:

• chr2-232379275-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001632.5(ALPP):​c.269C>G​(p.Pro90Arg) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALPP NM_001632.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.593

Genes affected

ALPP (HGNC:439): (alkaline phosphatase, placental) The protein encoded by this gene is an alkaline phosphatase, a metalloenzyme that catalyzes the hydrolysis of phosphoric acid monoesters. It belongs to a multigene family composed of four alkaline phosphatase isoenzymes. The enzyme functions as a homodimer and has a catalytic site containing one magnesium and two zinc ions, which are required for its enzymatic function. One of the main sources of this enzyme is the liver, and thus, it's one of several indicators of liver injury in different clinical conditions. In pregnant women, this protein is primarily expressed in placental and endometrial tissue, however, strong ectopic expression has been detected in ovarian adenocarcinoma, serous cystadenocarcinoma, and other ovarian cancer cells. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37698054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALPP	NM_001632.5	c.269C>G	p.Pro90Arg	missense_variant	3/11	ENST00000392027.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALPP	ENST00000392027.3	c.269C>G	p.Pro90Arg	missense_variant	3/11	1	NM_001632.5	P1
ALPP	ENST00000474529.1	n.348C>G		non_coding_transcript_exon_variant	3/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 74

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The c.269C>G (p.P90R) alteration is located in exon 3 (coding exon 3) of the ALPP gene. This alteration results from a C to G substitution at nucleotide position 269, causing the proline (P) at amino acid position 90 to be replaced by an arginine (R). 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	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Benign	0.71
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.33
Sift	Benign	0.58	T
Sift4G	Benign	0.58	T
Polyphen		0.77	P
Vest4		0.31
MutPred		0.50		Gain of MoRF binding (P = 0.0159);
MVP		0.91
MPC		0.090
ClinPred		0.46	T
GERP RS		0.44
Varity_R		0.26
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: chr2-233243985;