rs62185645

Variant names:

• chr2-196870955-G-C
• rs62185645
• NM_024989.4:c.1753C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024989.4(PGAP1):​c.1753C>G​(p.Gln585Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0054 in 1,606,892 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q585Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (31 hom.)
• Consequence: PGAP1 NM_024989.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 5.74
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0069019794).
• BP6: Variant 2-196870955-G-C is Benign according to our data. Variant chr2-196870955-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00396 (603/152166) while in subpopulation NFE AF = 0.0069 (469/68012). AF 95% confidence interval is 0.00638. There are 4 homozygotes in GnomAd4. There are 296 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.1753C>G	p.Gln585Glu	missense	Exon 19 of 27	NP_079265.2
	PGAP1	NM_001321099.2		c.1231C>G	p.Gln411Glu	missense	Exon 20 of 28	NP_001308028.1	Q75T13-2
	PGAP1	NM_001321100.2		c.586C>G	p.Gln196Glu	missense	Exon 18 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.1753C>G	p.Gln585Glu	missense	Exon 19 of 27	ENSP00000346809.3	Q75T13-1
	PGAP1	ENST00000423035.5	TSL:1	n.*1684C>G		non_coding_transcript_exon	Exon 20 of 28	ENSP00000415405.1	F8WD75
	PGAP1	ENST00000423035.5	TSL:1	n.*1684C>G		3_prime_UTR	Exon 20 of 28	ENSP00000415405.1	F8WD75

Frequencies

GnomAD3 genomes AF: 0.00397 AC: 603 AN: 152048 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00303

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00690

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00431 AC: 1079 AN: 250400 AF XY: 0.00432

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00131

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00774

Gnomad OTH exome AF: 0.00507

GnomAD4 exome AF: 0.00555 AC: 8076 AN: 1454726 Hom.: 31 Cov.: 28 AF XY: 0.00530 AC XY: 3836 AN XY: 724130

African (AFR) AF: 0.00105 AC: 35 AN: 33328

American (AMR) AF: 0.00148 AC: 66 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.0000767 AC: 2 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39514

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86026

European-Finnish (FIN) AF: 0.00491 AC: 261 AN: 53130

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5748

European-Non Finnish (NFE) AF: 0.00665 AC: 7359 AN: 1106126

Other (OTH) AF: 0.00580 AC: 349 AN: 60160

GnomAD4 genome AF: 0.00396 AC: 603 AN: 152166 Hom.: 4 Cov.: 32 AF XY: 0.00398 AC XY: 296 AN XY: 74386

African (AFR) AF: 0.00113 AC: 47 AN: 41510

American (AMR) AF: 0.00321 AC: 49 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00303 AC: 32 AN: 10574

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

European-Non Finnish (NFE) AF: 0.00690 AC: 469 AN: 68012

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00600 Hom.: 5

Bravo AF: 0.00411

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00752 AC: 29

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00507 AC: 616

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00705

EpiControl AF: 0.00730

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Intellectual disability, autosomal recessive 42 (2)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	22
DANN	Benign	0.77
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.00047
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		5.7
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.14
Sift	Benign	0.41	T
Sift4G	Uncertain	0.032	D
Polyphen		0.26	B
Vest4		0.51
MVP		0.65
MPC		0.27
ClinPred		0.0090	T
GERP RS		4.6
Varity_R		0.16
gMVP		0.75
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs62185645; hg19: chr2-197735679;