rs1048988

Variant names:

• chr2-232380220-G-C
• rs1048988
• NM_001632.5:c.692G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-232380220-G-C
• chr2-232380220-G-A
• chr2-232380220-G-T

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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
• Publications: 22 publications found

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]

ECEL1P2 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001632.5. 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
	ALPP	NM_001632.5	MANE Select	c.692G>C	p.Arg231Pro	missense	Exon 6 of 11	NP_001623.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALPP	ENST00000392027.3	TSL:1 MANE Select	c.692G>C	p.Arg231Pro	missense	Exon 6 of 11	ENSP00000375881.2	P05187
	ECEL1P2	ENST00000439072.1	TSL:5	n.158-263C>G		intron	N/A
	ECEL1P2	ENST00000441266.5	TSL:3	n.358-462C>G		intron	N/A

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

GnomAD2 exomes AF: 0.213 AC: 52693 AN: 247496 AF XY: 0.220

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 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

African (AFR) AF: 0.0814 AC: 2332 AN: 28634

American (AMR) AF: 0.177 AC: 7676 AN: 43258

Ashkenazi Jewish (ASJ) AF: 0.299 AC: 7381 AN: 24716

East Asian (EAS) AF: 0.0449 AC: 1569 AN: 34932

South Asian (SAS) AF: 0.214 AC: 17862 AN: 83576

European-Finnish (FIN) AF: 0.225 AC: 11585 AN: 51378

Middle Eastern (MID) AF: 0.265 AC: 1475 AN: 5568

European-Non Finnish (NFE) AF: 0.278 AC: 304243 AN: 1093420

Other (OTH) AF: 0.250 AC: 14543 AN: 58232

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

African (AFR) AF: 0.110 AC: 3676 AN: 33504

American (AMR) AF: 0.198 AC: 2871 AN: 14476

Ashkenazi Jewish (ASJ) AF: 0.324 AC: 1051 AN: 3248

East Asian (EAS) AF: 0.0479 AC: 224 AN: 4672

South Asian (SAS) AF: 0.213 AC: 987 AN: 4628

European-Finnish (FIN) AF: 0.231 AC: 2345 AN: 10158

Middle Eastern (MID) AF: 0.306 AC: 87 AN: 284

European-Non Finnish (NFE) AF: 0.290 AC: 18972 AN: 65512

Other (OTH) AF: 0.245 AC: 485 AN: 1976

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		2.9
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
Mutation Taster		=74/26	polymorphism (auto)

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

Other links and lift over

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