Genetic Variant NM_153747.2:c.676C>T (chr1-172441947-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_153747.2(PIGC):c.676C>T(p.Arg226Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00867 in 1,614,166 control chromosomes in the GnomAD database, including 82 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R226Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0061 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0089 ( 77 hom. )

Consequence

PIGC
NM_153747.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.565

Publications

9 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 -14 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=0.004669845).

BP6

Variant 1-172441947-G-A is Benign according to our data. Variant chr1-172441947-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 769251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

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.676C>T	p.Arg226Trp	missense	Exon 2 of 2	NP_714969.1	Q92535
C1orf105	NM_139240.4	MANE Select	c.22-3126G>A		intron	N/A	NP_640333.3
PIGC	NM_002642.4		c.676C>T	p.Arg226Trp	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.676C>T	p.Arg226Trp	missense	Exon 2 of 2	ENSP00000356701.3	Q92535
C1orf105	ENST00000367727.9	TSL:1 MANE Select	c.22-3126G>A		intron	N/A	ENSP00000356700.4	O95561
PIGC	ENST00000484368.1	TSL:1	n.96+2041C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.00613

AC:

933

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00236

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00452

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00166

Gnomad FIN

AF:

0.00377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00565

AC:

1421

AN:

251346

AF XY:

0.00571

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00388

Gnomad NFE exome

AF:

0.00992

Gnomad OTH exome

AF:

0.00571

GnomAD4 exome

AF:

0.00894

AC:

13070

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00862

AC XY:

6272

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.00257

AC:

AN:

33480

American (AMR)

AF:

0.00275

AC:

123

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000689

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00109

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00378

AC:

202

AN:

53420

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0108

AC:

11969

AN:

1111990

Other (OTH)

AF:

0.00942

AC:

569

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

758

1516

2275

3033

3791

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

444

888

1332

1776

2220

<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:

0.00612

AC:

932

AN:

152300

Hom.:

Cov.:

AF XY:

0.00541

AC XY:

403

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00236

AC:

AN:

41572

American (AMR)

AF:

0.00445

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00166

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00377

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0104

AC:

705

AN:

68024

Other (OTH)

AF:

0.00521

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00929

Hom.:

Bravo

AF:

0.00605

TwinsUK

AF:

0.00998

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0110

AC:

ExAC

AF:

0.00568

AC:

690

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0119

EpiControl

AF:

0.0111

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.029

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.79

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.90

PhyloP100

0.56

PrimateAI

Benign

0.38

PROVEAN

Benign

0.56

REVEL

Benign

0.068

Sift

Benign

0.19

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.20

MVP

0.51

MPC

0.13

ClinPred

0.0033

GERP RS

1.4

Varity_R

0.050

gMVP

0.51

Mutation Taster

=100/0

polymorphism

(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