chr2-196842737-C-G

Variant names:

• chr2-196842737-C-G
• rs1202995401
• NM_024989.4:c.2614G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024989.4(PGAP1):​c.2614G>C​(p.Val872Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,396,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V872I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PGAP1 NM_024989.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.335
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07161203).

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.2614G>C	p.Val872Leu	missense	Exon 26 of 27	NP_079265.2
	PGAP1	NM_001321099.2		c.2092G>C	p.Val698Leu	missense	Exon 27 of 28	NP_001308028.1	Q75T13-2
	PGAP1	NM_001321100.2		c.1447G>C	p.Val483Leu	missense	Exon 25 of 26	NP_001308029.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGAP1	ENST00000354764.9	TSL:1 MANE Select	c.2614G>C	p.Val872Leu	missense	Exon 26 of 27	ENSP00000346809.3	Q75T13-1
	PGAP1	ENST00000423035.5	TSL:1	n.*2545G>C		non_coding_transcript_exon	Exon 27 of 28	ENSP00000415405.1	F8WD75
	PGAP1	ENST00000423035.5	TSL:1	n.*2545G>C		3_prime_UTR	Exon 27 of 28	ENSP00000415405.1	F8WD75

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000434 AC: 1 AN: 230480 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000336

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1396714 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 696088

African (AFR) AF: 0.00 AC: 0 AN: 31128

American (AMR) AF: 0.0000250 AC: 1 AN: 40066

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24930

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 37962

South Asian (SAS) AF: 0.00 AC: 0 AN: 77876

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52494

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5388

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069228

Other (OTH) AF: 0.00 AC: 0 AN: 57642

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	13
DANN	Benign	0.95
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	L
PhyloP100		0.34
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.083
Sift	Benign	0.38	T
Sift4G	Benign	0.18	T
Polyphen		0.020	B
Vest4		0.13
MutPred		0.49		Loss of sheet (P = 0.0315)
MVP		0.24
MPC		0.19
ClinPred		0.054	T
GERP RS		3.4
Varity_R		0.064
gMVP		0.20
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1202995401; hg19: chr2-197707461;