2-196926586-G-T

Variant names:

• chr2-196926586-G-T
• rs375123215
• NM_024989.4:c.31C>A

Variant summary

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

The NM_001321099.2(PGAP1):​c.-576C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PGAP1 NM_001321099.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.455
• Publications: 1 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=0.1611675).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001321099.2. 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.31C>A	p.Leu11Met	missense	Exon 1 of 27	NP_079265.2
	PGAP1	NM_001321099.2		c.-576C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 28	NP_001308028.1
	PGAP1	NM_001321100.2		c.-1081C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 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.31C>A	p.Leu11Met	missense	Exon 1 of 27	ENSP00000346809.3
	PGAP1	ENST00000423035.5	TSL:1	n.31C>A		non_coding_transcript_exon	Exon 1 of 28	ENSP00000415405.1
	PGAP1	ENST00000485830.1	TSL:1	n.207+1004C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251482 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000165 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	0.0072	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.46
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.088
Sift	Benign	0.037	D
Sift4G	Uncertain	0.034	D
Polyphen		0.84	P
Vest4		0.32
MutPred		0.25		Gain of sheet (P = 0.1945)
MVP		0.51
MPC		0.60
ClinPred		0.36	T
GERP RS		0.76
PromoterAI		0.39	Neutral
Varity_R		0.077
gMVP		0.68
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs375123215; hg19: chr2-197791310;