chr2-196870955-G-C

Position:

chr2-196870955-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024989.4(PGAP1):c.1753C>G(p.Gln585Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0054 in 1,606,892 control chromosomes in the GnomAD database, including 35 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0040 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 31 hom. )

Consequence

PGAP1
NM_024989.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.74

Variant links:

Genes affected

PGAP1 (HGNC:25712): (post-GPI attachment to proteins inositol deacylase 1) The protein encoded by this gene functions early in the glycosylphosphatidylinositol (GPI) biosynthetic pathway, catalyzing the inositol deacylation of GPI. The encoded protein is required for the production of GPI that can attach to proteins, and this may be an important factor in the transport of GPI-anchored proteins from the endoplasmic reticulum to the Golgi. Defects in this gene are a cause an autosomal recessive form of cognitive impairment. [provided by RefSeq, Jul 2017]

PGAP1 links:

PGAP1 (HGNC:):

PGAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0069019794).

BP6

Variant 2-196870955-G-C is Benign according to our data. Variant chr2-196870955-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 436291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-196870955-G-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00396 (603/152166) while in subpopulation NFE AF= 0.0069 (469/68012). AF 95% confidence interval is 0.00638. There are 4 homozygotes in gnomad4. There are 296 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGAP1	NM_024989.4 linkuse as main transcript	c.1753C>G	p.Gln585Glu	missense_variant	19/27	ENST00000354764.9	NP_079265.2	Q75T13-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGAP1	ENST00000354764.9 linkuse as main transcript	c.1753C>G	p.Gln585Glu	missense_variant	19/27	1	NM_024989.4	ENSP00000346809.3		Q75T13-1

Frequencies

GnomAD3 genomes

AF:

0.00397

AC:

603

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00303

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00690

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00431

AC:

1079

AN:

250400

Hom.:

AF XY:

0.00432

AC XY:

585

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.00136

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00476

Gnomad NFE exome

AF:

0.00774

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.00555

AC:

8076

AN:

1454726

Hom.:

Cov.:

AF XY:

0.00530

AC XY:

3836

AN XY:

724130

show subpopulations

Gnomad4 AFR exome

AF:

0.00105

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.0000767

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00491

Gnomad4 NFE exome

AF:

0.00665

Gnomad4 OTH exome

AF:

0.00580

GnomAD4 genome

AF:

0.00396

AC:

603

AN:

152166

Hom.:

Cov.:

AF XY:

0.00398

AC XY:

296

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00321

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00303

Gnomad4 NFE

AF:

0.00690

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00600

Hom.:

Bravo

AF:

0.00411

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00507

AC:

616

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00705

EpiControl

AF:

0.00730

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PGAP1: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 19, 2017	- -

Intellectual disability, autosomal recessive 42

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 02, 2017

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.071

T;.

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.00047

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.85

D;D

M_CAP

Benign

0.0036

MetaRNN

Benign

0.0069

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

L;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-0.53

N;N

REVEL

Benign

0.14

Sift

Benign

0.41

T;T

Sift4G

Uncertain

0.032

D;T

Polyphen

0.26

B;B

Vest4

0.51

MVP

0.65

MPC

0.27

ClinPred

0.0090

GERP RS

4.6

Varity_R

0.16

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over