2-196897152-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_024989.4(PGAP1):c.906T>C(p.Leu302Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0047 in 1,578,116 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 22 hom. )

Consequence

PGAP1
NM_024989.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.850

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 42
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive spastic paraplegia type 67
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PGAP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 2-196897152-A-G is Benign according to our data. Variant chr2-196897152-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.85 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0027 (412/152328) while in subpopulation NFE AF = 0.00479 (326/68012). AF 95% confidence interval is 0.00437. There are 1 homozygotes in GnomAd4. There are 194 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGAP1	NM_024989.4 link	c.906T>C	p.Leu302Leu	synonymous_variant	Exon 7 of 27	ENST00000354764.9	NP_079265.2	Q75T13-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGAP1	ENST00000354764.9 link	c.906T>C	p.Leu302Leu	synonymous_variant	Exon 7 of 27	1	NM_024989.4	ENSP00000346809.3		Q75T13-1

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

412

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00479

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00220

AC:

513

AN:

233676

AF XY:

0.00219

show subpopulations

Gnomad AFR exome

AF:

0.000899

Gnomad AMR exome

AF:

0.000824

Gnomad ASJ exome

AF:

0.00266

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000655

Gnomad NFE exome

AF:

0.00377

Gnomad OTH exome

AF:

0.00175

GnomAD4 exome

AF:

0.00492

AC:

7011

AN:

1425788

Hom.:

Cov.:

AF XY:

0.00467

AC XY:

3317

AN XY:

709536

show subpopulations

African (AFR)

AF:

0.000775

AC:

AN:

32246

American (AMR)

AF:

0.000704

AC:

AN:

41192

Ashkenazi Jewish (ASJ)

AF:

0.00271

AC:

AN:

25452

East Asian (EAS)

AF:

0.0000257

AC:

AN:

38962

South Asian (SAS)

AF:

0.000987

AC:

AN:

81018

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

52982

Middle Eastern (MID)

AF:

0.000351

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.00591

AC:

6436

AN:

1089022

Other (OTH)

AF:

0.00530

AC:

314

AN:

59212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

276

553

829

1106

1382

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

250

500

750

1000

1250

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00270

AC:

412

AN:

152328

Hom.:

Cov.:

AF XY:

0.00260

AC XY:

194

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41586

American (AMR)

AF:

0.00111

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00166

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00479

AC:

326

AN:

68012

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

105

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00375

Hom.:

Bravo

AF:

0.00279

Asia WGS

AF:

0.000289

AC:

AN:

3468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 22, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Jan 04, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PGAP1: BP4, BP7, BS2 -

Intellectual disability, autosomal recessive 42

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

7.7

(source)

DANN

Benign

0.74

PhyloP100

0.85

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over