chr2-232379003-G-C

Position:

• chr2-232379003-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001632.5(ALPP):​c.109G>C​(p.Glu37Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,613,576 control chromosomes in the GnomAD database, including 229 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (39 hom., cov: 32)
  • Exomes 𝑓: 0.012 (190 hom.)
• Consequence: ALPP NM_001632.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.262

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]

ALPP (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040620863).
• BP6: Variant 2-232379003-G-C is Benign according to our data. Variant chr2-232379003-G-C is described in ClinVar as [Benign]. Clinvar id is 773651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0176 (2680/152104) while in subpopulation AFR AF= 0.0345 (1429/41388). AF 95% confidence interval is 0.033. There are 39 homozygotes in gnomad4. There are 1233 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 39 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALPP	NM_001632.5	c.109G>C	p.Glu37Gln	missense_variant	2/11	ENST00000392027.3	NP_001623.3
LOC124906123	XR_007088121.1	n.30C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALPP	ENST00000392027.3	c.109G>C	p.Glu37Gln	missense_variant	2/11	1	NM_001632.5	ENSP00000375881.2
ALPP	ENST00000474529.1	n.188G>C		non_coding_transcript_exon_variant	2/4	2

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2679 AN: 151986 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0345

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0311

Gnomad SAS AF: 0.0345

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.0147 AC: 3701 AN: 251054 Hom.: 48 AF XY: 0.0152 AC XY: 2066 AN XY: 135754

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.00437

Gnomad ASJ exome AF: 0.00337

Gnomad EAS exome AF: 0.0347

Gnomad SAS exome AF: 0.0324

Gnomad FIN exome AF: 0.00481

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0121 AC: 17643 AN: 1461472 Hom.: 190 Cov.: 92 AF XY: 0.0125 AC XY: 9080 AN XY: 727006

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.0300

Gnomad4 SAS exome AF: 0.0291

Gnomad4 FIN exome AF: 0.00440

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0176 AC: 2680 AN: 152104 Hom.: 39 Cov.: 32 AF XY: 0.0166 AC XY: 1233 AN XY: 74370

Gnomad4 AFR AF: 0.0345

Gnomad4 AMR AF: 0.00981

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0310

Gnomad4 SAS AF: 0.0343

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00320 Hom.: 2

Bravo AF: 0.0184

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00701 AC: 27

ExAC AF: 0.0160 AC: 1941

EpiCase AF: 0.00883

EpiControl AF: 0.00966

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	Sep 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.080
DANN	Benign	0.83
DEOGEN2	Benign	0.034	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0030	N
LIST_S2	Benign	0.011	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-2.5	N
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.054
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.049
MPC		0.079
ClinPred		0.0070	T
GERP RS		-0.81
Varity_R		0.15
gMVP		0.61

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: rs113323105; hg19: chr2-233243713; COSMIC: COSV67396445; COSMIC: COSV67396445;