2-196842747-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024989.4(PGAP1):c.2604T>C(p.Asn868=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00179 in 1,576,724 control chromosomes in the GnomAD database, including 36 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (13 hom.)
• Consequence: PGAP1 NM_024989.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.502

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 2-196842747-A-G is Benign according to our data. Variant chr2-196842747-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 703891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.502 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0101 (1535/152200) while in subpopulation AFR AF= 0.0349 (1452/41562). AF 95% confidence interval is 0.0334. There are 23 homozygotes in gnomad4. There are 721 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4	c.2604T>C	p.Asn868=	synonymous_variant	26/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9	c.2604T>C	p.Asn868=	synonymous_variant	26/27	1	NM_024989.4	P1

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1535 AN: 152082 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0350

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00260 AC: 622 AN: 239678 Hom.: 15 AF XY: 0.00206 AC XY: 267 AN XY: 129850

Gnomad AFR exome AF: 0.0361

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000547

Gnomad OTH exome AF: 0.00139

GnomAD4 exome AF: 0.000909 AC: 1295 AN: 1424524 Hom.: 13 Cov.: 26 AF XY: 0.000774 AC XY: 549 AN XY: 709720

Gnomad4 AFR exome AF: 0.0338

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000855

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000184

Gnomad4 OTH exome AF: 0.00189

GnomAD4 genome AF: 0.0101 AC: 1535 AN: 152200 Hom.: 23 Cov.: 32 AF XY: 0.00969 AC XY: 721 AN XY: 74418

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00994

Alfa AF: 0.00403 Hom.: 6

Bravo AF: 0.0118

Asia WGS AF: 0.000582 AC: 2 AN: 3452

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2018

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2021

- -

Intellectual disability, autosomal recessive 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

PGAP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	7.1
Dann	Benign	0.69

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: rs74459402; hg19: chr2-197707471;