2-232380220-G-C

Position:

• chr2-232380220-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001632.5(ALPP):​c.692G>C​(p.Arg231Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.256 in 1,563,082 control chromosomes in the GnomAD database, including 52,638 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.22 (3730 hom., cov: 33)
  • Exomes 𝑓: 0.26 (48908 hom.)
• Consequence: ALPP NM_001632.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.94

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]

ENSG00000224516 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004609227).
• BP6: Variant 2-232380220-G-C is Benign according to our data. Variant chr2-232380220-G-C is described in ClinVar as [Benign]. Clinvar id is 767868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPP	NM_001632.5	c.692G>C	p.Arg231Pro	missense_variant	6/11	ENST00000392027.3	NP_001623.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPP	ENST00000392027.3	c.692G>C	p.Arg231Pro	missense_variant	6/11	1	NM_001632.5	ENSP00000375881.2
ENSG00000224516	ENST00000439072.1	n.158-263C>G		intron_variant		5
ENSG00000224516	ENST00000441266.5	n.358-462C>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.224 AC: 31142 AN: 139268 Hom.: 3729 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.486

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.324

Gnomad EAS AF: 0.0483

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.290

Gnomad OTH AF: 0.247

GnomAD3 exomes AF: 0.213 AC: 52693 AN: 247496 Hom.: 6503 AF XY: 0.220 AC XY: 29426 AN XY: 133930

Gnomad AFR exome AF: 0.0663

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.274

Gnomad EAS exome AF: 0.0348

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.270

Gnomad OTH exome AF: 0.232

GnomAD4 exome AF: 0.259 AC: 368666 AN: 1423714 Hom.: 48908 Cov.: 109 AF XY: 0.258 AC XY: 183074 AN XY: 708312

Gnomad4 AFR exome AF: 0.0814

Gnomad4 AMR exome AF: 0.177

Gnomad4 ASJ exome AF: 0.299

Gnomad4 EAS exome AF: 0.0449

Gnomad4 SAS exome AF: 0.214

Gnomad4 FIN exome AF: 0.225

Gnomad4 NFE exome AF: 0.278

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.223 AC: 31140 AN: 139368 Hom.: 3730 Cov.: 33 AF XY: 0.221 AC XY: 15047 AN XY: 68176

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.324

Gnomad4 EAS AF: 0.0479

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.290

Gnomad4 OTH AF: 0.245

Alfa AF: 0.219 Hom.: 1244

ESP6500AA AF: 0.0654 AC: 288

ESP6500EA AF: 0.254 AC: 2180

ExAC AF: 0.212 AC: 25684

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.090
DANN	Benign	0.57
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.46	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	-3.7	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	7.6	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.058
MPC		0.94
ClinPred		0.0057	T
GERP RS		0.32
Varity_R		0.32
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs1048988; hg19: chr2-233244930; COSMIC: COSV67395542; COSMIC: COSV67395542;