2-196841269-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_024989.4(PGAP1):c.2734C>T(p.Pro912Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000403 in 1,613,580 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00040 (3 hom.)
• Consequence: PGAP1 NM_024989.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.88

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007525414).
• BP6: Variant 2-196841269-G-A is Benign according to our data. Variant chr2-196841269-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1164203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000404 (591/1461510) while in subpopulation AMR AF= 0.00134 (60/44678). AF 95% confidence interval is 0.00107. There are 3 homozygotes in gnomad4_exome. There are 288 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGAP1	NM_024989.4	c.2734C>T	p.Pro912Ser	missense_variant	27/27	ENST00000354764.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGAP1	ENST00000354764.9	c.2734C>T	p.Pro912Ser	missense_variant	27/27	1	NM_024989.4	P1
PGAP1	ENST00000423035.5	c.*2665C>T		3_prime_UTR_variant, NMD_transcript_variant	28/28	1
PGAP1	ENST00000422444.1	c.445C>T	p.Pro149Ser	missense_variant	4/4	2
PGAP1	ENST00000459896.5	n.105+1452C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000388 AC: 59 AN: 152070 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000849 AC: 213 AN: 250980 Hom.: 0 AF XY: 0.000826 AC XY: 112 AN XY: 135638

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00136

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000220

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.000404 AC: 591 AN: 1461510 Hom.: 3 Cov.: 30 AF XY: 0.000396 AC XY: 288 AN XY: 727048

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00134

Gnomad4 ASJ exome AF: 0.0132

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000113

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.000388 AC: 59 AN: 152070 Hom.: 0 Cov.: 32 AF XY: 0.000350 AC XY: 26 AN XY: 74286

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000797 Hom.: 1

Bravo AF: 0.000502

ExAC AF: 0.000791 AC: 96

EpiCase AF: 0.000545

EpiControl AF: 0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 01, 2019

- -

Intellectual disability, autosomal recessive 42 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	16
Dann	Uncertain	1.0
DEOGEN2	Benign	0.052	T;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;.
MutationTaster	Benign	0.91	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.28	N;D
REVEL	Benign	0.083
Sift	Benign	0.59	T;T
Sift4G	Benign	0.71	T;D
Polyphen		0.043	B;.
Vest4		0.15
MVP		0.52
MPC		0.20
ClinPred		0.043	T
GERP RS		4.0
Varity_R		0.060
gMVP		0.26

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

Publications

LitVar

Other links and lift over

dbSNP: rs147312612; hg19: chr2-197705993;