11-3825023-C-T

Variant names:

• chr11-3825023-C-T
• rs117338939
• NM_014489.4:c.712C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM5 BP4_Strong BS1_Supporting

The NM_014489.4(PGAP2):​c.712C>T​(p.Arg238Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00073 in 1,614,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (1 hom.)
• Consequence: PGAP2 NM_014489.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.75
• Publications: 6 publications found

Genes affected

PGAP2 (HGNC:17893): (post-GPI attachment to proteins 2) The protein encoded by this gene plays a role in the maturation of glycosylphosphatidylinositol (GPI) anchors on GPI-anchored proteins. Mutations in this gene are associated with an autosomal recessive syndrome characterized by hyperphosphatasia and intellectual disability. [provided by RefSeq, Jul 2017]

PGAP2 Gene-Disease associations (from GenCC):

• hyperphosphatasia with intellectual disability syndrome 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• hyperphosphatasia-intellectual disability syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-3825024-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 50503.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0274072).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000499 (76/152292) while in subpopulation NFE AF = 0.000823 (56/68032). AF 95% confidence interval is 0.000651. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014489.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	NM_014489.4	MANE Select	c.712C>T	p.Arg238Cys	missense	Exon 6 of 7	NP_055304.1
	PGAP2	NM_001256236.2		c.712C>T	p.Arg238Cys	missense	Exon 7 of 8	NP_001243165.2
	PGAP2	NM_001346397.2		c.682C>T	p.Arg228Cys	missense	Exon 6 of 7	NP_001333326.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP2	ENST00000278243.9	TSL:1 MANE Select	c.712C>T	p.Arg238Cys	missense	Exon 6 of 7	ENSP00000278243.4
	PGAP2	ENST00000300730.10	TSL:1	c.688C>T	p.Arg230Cys	missense	Exon 6 of 7	ENSP00000300730.6
	PGAP2	ENST00000396993.8	TSL:1	c.61C>T	p.Arg21Cys	missense	Exon 5 of 6	ENSP00000380190.6

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000422 AC: 106 AN: 251420 AF XY: 0.000346

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000826

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000755 AC: 1103 AN: 1461834 Hom.: 1 Cov.: 32 AF XY: 0.000715 AC XY: 520 AN XY: 727224

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000176 AC: 7 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86252

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000949 AC: 1055 AN: 1111968

Other (OTH) AF: 0.000480 AC: 29 AN: 60394

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74458

African (AFR) AF: 0.000361 AC: 15 AN: 41554

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68032

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000607 Hom.: 0

Bravo AF: 0.000453

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000654

EpiControl AF: 0.000533

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Dec 21, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 177 of the PGAP2 protein (p.Arg177Cys). This variant is present in population databases (rs117338939, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with PGAP2-related conditions. ClinVar contains an entry for this variant (Variation ID: 377014). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PGAP2 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Dec 05, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Uncertain:1

Aug 06, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.712C>T (p.R238C) alteration is located in exon 6 (coding exon 5) of the PGAP2 gene. This alteration results from a C to T substitution at nucleotide position 712, causing the arginine (R) at amino acid position 238 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	27
DANN	Benign	0.94
DEOGEN2	Uncertain	0.72	D
Eigen	Benign	0.034
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.7
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.14
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.088	T
Polyphen		0.049	B
Vest4		0.38
MVP		0.43
MPC		0.52
ClinPred		0.047	T
GERP RS		5.3
Varity_R		0.13
gMVP		0.55
Mutation Taster		=61/39	polymorphism

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: rs117338939; hg19: chr11-3846253; COSMIC: COSV53467717; COSMIC: COSV53467717;