2-196842521-GA-GAA

Variant names:

• chr2-196842521-G-GA
• rs200071090
• NM_024989.4:c.2630+199dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_024989.4(PGAP1):​c.2630+199dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 148,976 control chromosomes in the GnomAD database, including 24 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.015 (24 hom., cov: 32)
• Consequence: PGAP1 NM_024989.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.664
• Publications: 0 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 -10 ACMG points.

• BP6: Variant 2-196842521-G-GA is Benign according to our data. Variant chr2-196842521-G-GA is described in ClinVar as Likely_benign. ClinVar VariationId is 1204985.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0154 (2288/148976) while in subpopulation SAS AF = 0.0519 (246/4736). AF 95% confidence interval is 0.0466. There are 24 homozygotes in GnomAd4. There are 1138 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP1	NM_024989.4	MANE Select	c.2630+199dupT		intron	N/A	NP_079265.2
	PGAP1	NM_001321099.2		c.2108+199dupT		intron	N/A	NP_001308028.1	Q75T13-2
	PGAP1	NM_001321100.2		c.1463+199dupT		intron	N/A	NP_001308029.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP1	ENST00000354764.9	TSL:1 MANE Select	c.2630+199_2630+200insT		intron	N/A	ENSP00000346809.3	Q75T13-1
	PGAP1	ENST00000423035.5	TSL:1	n.*2561+199_*2561+200insT		intron	N/A	ENSP00000415405.1	F8WD75
	PGAP1	ENST00000961224.1		c.2723+199_2723+200insT		intron	N/A	ENSP00000631283.1

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2290 AN: 148872 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00376

Gnomad AMI AF: 0.0330

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0290

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.0519

Gnomad FIN AF: 0.00995

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0214

Gnomad OTH AF: 0.0151

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0154 AC: 2288 AN: 148976 Hom.: 24 Cov.: 32 AF XY: 0.0157 AC XY: 1138 AN XY: 72548

African (AFR) AF: 0.00374 AC: 152 AN: 40594

American (AMR) AF: 0.0124 AC: 185 AN: 14974

Ashkenazi Jewish (ASJ) AF: 0.0290 AC: 100 AN: 3444

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5096

South Asian (SAS) AF: 0.0519 AC: 246 AN: 4736

European-Finnish (FIN) AF: 0.00995 AC: 97 AN: 9744

Middle Eastern (MID) AF: 0.0411 AC: 12 AN: 292

European-Non Finnish (NFE) AF: 0.0214 AC: 1434 AN: 67114

Other (OTH) AF: 0.0145 AC: 30 AN: 2074

Alfa AF: 0.00793 Hom.: 1

Bravo AF: 0.0132

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.66
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs200071090; hg19: chr2-197707245; COSMIC: COSV61326142; COSMIC: COSV61326142;