rs149815494

Variant names:

• chr2-196847146-G-A
• rs149815494
• NM_024989.4:c.2007C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024989.4(PGAP1):​c.2007C>T​(p.Ala669Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0134 in 1,612,652 control chromosomes in the GnomAD database, including 320 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (37 hom., cov: 32)
  • Exomes 𝑓: 0.013 (283 hom.)
• Consequence: PGAP1 NM_024989.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.11
• Publications: 3 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 2-196847146-G-A is Benign according to our data. Variant chr2-196847146-G-A is described in ClinVar as Benign. ClinVar VariationId is 474991.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.11 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0129 (1964/152008) while in subpopulation NFE AF = 0.0128 (869/67966). AF 95% confidence interval is 0.0121. There are 37 homozygotes in GnomAd4. There are 1163 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024989.4. 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
	PGAP1	NM_024989.4	MANE Select	c.2007C>T	p.Ala669Ala	synonymous	Exon 22 of 27	NP_079265.2
	PGAP1	NM_001321099.2		c.1485C>T	p.Ala495Ala	synonymous	Exon 23 of 28	NP_001308028.1
	PGAP1	NM_001321100.2		c.840C>T	p.Ala280Ala	synonymous	Exon 21 of 26	NP_001308029.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP1	ENST00000354764.9	TSL:1 MANE Select	c.2007C>T	p.Ala669Ala	synonymous	Exon 22 of 27	ENSP00000346809.3
	PGAP1	ENST00000423035.5	TSL:1	n.*1938C>T		non_coding_transcript_exon	Exon 23 of 28	ENSP00000415405.1
	PGAP1	ENST00000423035.5	TSL:1	n.*1938C>T		3_prime_UTR	Exon 23 of 28	ENSP00000415405.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1964 AN: 151890 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00193

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.00407

Gnomad ASJ AF: 0.00518

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.0843

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0128

Gnomad OTH AF: 0.0101

GnomAD2 exomes AF: 0.0136 AC: 3392 AN: 249556 AF XY: 0.0134

Gnomad AFR exome AF: 0.00174

Gnomad AMR exome AF: 0.00368

Gnomad ASJ exome AF: 0.00451

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.0811

Gnomad NFE exome AF: 0.0121

Gnomad OTH exome AF: 0.0125

GnomAD4 exome AF: 0.0134 AC: 19565 AN: 1460644 Hom.: 283 Cov.: 30 AF XY: 0.0129 AC XY: 9347 AN XY: 726646

African (AFR) AF: 0.00161 AC: 54 AN: 33458

American (AMR) AF: 0.00391 AC: 175 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00459 AC: 120 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39630

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.0757 AC: 4028 AN: 53208

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.0131 AC: 14593 AN: 1111164

Other (OTH) AF: 0.00981 AC: 592 AN: 60348

GnomAD4 genome AF: 0.0129 AC: 1964 AN: 152008 Hom.: 37 Cov.: 32 AF XY: 0.0157 AC XY: 1163 AN XY: 74294

African (AFR) AF: 0.00193 AC: 80 AN: 41492

American (AMR) AF: 0.00406 AC: 62 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00518 AC: 18 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4808

European-Finnish (FIN) AF: 0.0843 AC: 886 AN: 10508

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

European-Non Finnish (NFE) AF: 0.0128 AC: 869 AN: 67966

Other (OTH) AF: 0.00997 AC: 21 AN: 2106

Alfa AF: 0.00965 Hom.: 4

Bravo AF: 0.00661

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PGAP1: BP4, BP7, BS1, BS2

Feb 13, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Hereditary spastic paraplegia Benign:1

Aug 30, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability, autosomal recessive 42 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.35
PhyloP100		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs149815494; hg19: chr2-197711870;