Genetic Variant PIGC:p.Pro266Ser (chr1-172441827-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_153747.2(PIGC):c.796C>T(p.Pro266Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.547 in 1,613,024 control chromosomes in the GnomAD database, including 249,558 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.45 ( 18407 hom., cov: 33)

Exomes 𝑓: 0.56 ( 231151 hom. )

Consequence

PIGC
NM_153747.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 9.19

Publications

55 publications found

Variant links:

Genes affected

PIGC (HGNC:8960): (phosphatidylinositol glycan anchor biosynthesis class C) This gene encodes an endoplasmic reticulum associated protein that is involved in glycosylphosphatidylinositol (GPI) lipid anchor biosynthesis. The GPI lipid anchor is a glycolipid found on many blood cells and serves to anchor proteins to the cell surface. The encoded protein is one subunit of the GPI N-acetylglucosaminyl (GlcNAc) transferase that transfers GlcNAc to phosphatidylinositol (PI) on the cytoplasmic side of the endoplasmic reticulum. Two alternatively spliced transcripts that encode the same protein have been found for this gene. A pseudogene on chromosome 11 has also been characterized. [provided by RefSeq, Jul 2008]

PIGC links:

C1orf105 (HGNC:29591): (chromosome 1 open reading frame 105)

C1orf105 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a chain Phosphatidylinositol N-acetylglucosaminyltransferase subunit C (size 296) in uniprot entity PIGC_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_153747.2

BP4

Computational evidence support a benign effect (MetaRNN=1.0123705E-4).

BP6

Variant 1-172441827-G-A is Benign according to our data. Variant chr1-172441827-G-A is described in ClinVar as Benign. ClinVar VariationId is 1327021.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.63 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153747.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIGC	NM_153747.2	MANE Select	c.796C>T	p.Pro266Ser	missense	Exon 2 of 2	NP_714969.1	Q92535
C1orf105	NM_139240.4	MANE Select	c.22-3246G>A		intron	N/A	NP_640333.3
PIGC	NM_002642.4		c.796C>T	p.Pro266Ser	missense	Exon 2 of 2	NP_002633.1	Q92535

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIGC	ENST00000344529.5	TSL:1 MANE Select	c.796C>T	p.Pro266Ser	missense	Exon 2 of 2	ENSP00000356701.3	Q92535
C1orf105	ENST00000367727.9	TSL:1 MANE Select	c.22-3246G>A		intron	N/A	ENSP00000356700.4	O95561
PIGC	ENST00000484368.1	TSL:1	n.96+2161C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.452

AC:

68708

AN:

152014

Hom.:

18418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.629

Gnomad AMR

AF:

0.553

Gnomad ASJ

AF:

0.529

Gnomad EAS

AF:

0.648

Gnomad SAS

AF:

0.575

Gnomad FIN

AF:

0.581

Gnomad MID

AF:

0.585

Gnomad NFE

AF:

0.566

Gnomad OTH

AF:

0.497

GnomAD2 exomes

AF:

0.557

AC:

139685

AN:

250962

AF XY:

0.564

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.619

Gnomad ASJ exome

AF:

0.544

Gnomad EAS exome

AF:

0.648

Gnomad FIN exome

AF:

0.591

Gnomad NFE exome

AF:

0.573

Gnomad OTH exome

AF:

0.577

GnomAD4 exome

AF:

0.557

AC:

814280

AN:

1460892

Hom.:

231151

Cov.:

AF XY:

0.560

AC XY:

406872

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.127

AC:

4248

AN:

33464

American (AMR)

AF:

0.611

AC:

27291

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

14334

AN:

26108

East Asian (EAS)

AF:

0.651

AC:

25837

AN:

39690

South Asian (SAS)

AF:

0.574

AC:

49460

AN:

86164

European-Finnish (FIN)

AF:

0.590

AC:

31514

AN:

53404

Middle Eastern (MID)

AF:

0.580

AC:

3341

AN:

5764

European-Non Finnish (NFE)

AF:

0.563

AC:

625663

AN:

1111312

Other (OTH)

AF:

0.540

AC:

32592

AN:

60348

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

18773

37547

56320

75094

93867

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17370

34740

52110

69480

86850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.452

AC:

68700

AN:

152132

Hom.:

18407

Cov.:

AF XY:

0.457

AC XY:

34013

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.142

AC:

5902

AN:

41516

American (AMR)

AF:

0.553

AC:

8456

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.529

AC:

1834

AN:

3468

East Asian (EAS)

AF:

0.648

AC:

3358

AN:

5180

South Asian (SAS)

AF:

0.575

AC:

2774

AN:

4822

European-Finnish (FIN)

AF:

0.581

AC:

6145

AN:

10568

Middle Eastern (MID)

AF:

0.568

AC:

167

AN:

294

European-Non Finnish (NFE)

AF:

0.566

AC:

38454

AN:

67972

Other (OTH)

AF:

0.491

AC:

1036

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1690

3381

5071

6762

8452

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

622

1244

1866

2488

3110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.535

Hom.:

104222

Bravo

AF:

0.438

TwinsUK

AF:

0.550

AC:

2040

ALSPAC

AF:

0.563

AC:

2168

ESP6500AA

AF:

0.151

AC:

665

ESP6500EA

AF:

0.557

AC:

4793

ExAC

AF:

0.548

AC:

66498

Asia WGS

AF:

0.527

AC:

1836

AN:

3478

EpiCase

AF:

0.573

EpiControl

AF:

0.574

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Glycosylphosphatidylinositol biosynthesis defect 16 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.70

MetaRNN

Benign

0.00010

MetaSVM

Benign

-0.77

MutationAssessor

Benign

1.5

PhyloP100

9.2

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-6.1

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.90

MPC

0.57

ClinPred

0.042

GERP RS

4.2

Varity_R

0.72

gMVP

0.89

Mutation Taster

=82/18

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over