dbSNP rs200053998: PGA5:p.Lys222Gln (chr11-61248426-A-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_014224.5(PGA5):c.664A>C(p.Lys222Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00421 in 152,138 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0042 ( 14 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 31 hom. )

Failed GnomAD Quality Control

Consequence

PGA5
NM_014224.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.83

Publications

5 publications found

Variant links:

Genes affected

PGA5 (HGNC:8887): (pepsinogen A5) This gene encodes a protein precursor of the digestive enzyme pepsin, a member of the peptidase A1 family of endopeptidases. The encoded precursor is secreted by gastric chief cells and undergoes autocatalytic cleavage in acidic conditions to form the active enzyme, which functions in the digestion of dietary proteins. This gene is found in a cluster of related genes on chromosome 11, each of which encodes one of multiple pepsinogens. Pepsinogen levels in serum may serve as a biomarker for atrophic gastritis and gastric cancer. [provided by RefSeq, Jul 2015]

PGA5 links:

ENSG00000256220 (HGNC:):

ENSG00000256220 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047968924).

BP6

Variant 11-61248426-A-C is Benign according to our data. Variant chr11-61248426-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2641821.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014224.5. 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
	PGA5	NM_014224.5	MANE Select	c.664A>C	p.Lys222Gln	missense	Exon 6 of 9	NP_055039.1	P0DJD9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PGA5	ENST00000312403.10	TSL:1 MANE Select	c.664A>C	p.Lys222Gln	missense	Exon 6 of 9	ENSP00000309542.6	P0DJD9
PGA5	ENST00000451616.6	TSL:2	c.202A>C	p.Lys68Gln	missense	Exon 1 of 4	ENSP00000408739.2	C9JM59
ENSG00000256220	ENST00000537594.1	TSL:5	n.160A>C		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.00421

AC:

640

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00591

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00412

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00309

AC:

775

AN:

251000

AF XY:

0.00293

show subpopulations

Gnomad AFR exome

AF:

0.00432

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00476

Gnomad EAS exome

AF:

0.00109

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00366

Gnomad OTH exome

AF:

0.00652

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00194

AC:

2823

AN:

1456138

Hom.:

Cov.:

AF XY:

0.00194

AC XY:

1409

AN XY:

724632

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00375

AC:

125

AN:

33324

American (AMR)

AF:

0.00311

AC:

139

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00487

AC:

127

AN:

26074

East Asian (EAS)

AF:

0.00108

AC:

AN:

39692

South Asian (SAS)

AF:

0.000963

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00243

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00190

AC:

2100

AN:

1106830

Other (OTH)

AF:

0.00309

AC:

186

AN:

60154

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

173

346

519

692

865

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

150

200

250

<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:

0.00421

AC:

641

AN:

152138

Hom.:

Cov.:

AF XY:

0.00389

AC XY:

289

AN XY:

74386

show subpopulations

African (AFR)

AF:

0.00592

AC:

245

AN:

41408

American (AMR)

AF:

0.00379

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3472

East Asian (EAS)

AF:

0.00155

AC:

AN:

5176

South Asian (SAS)

AF:

0.000621

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00412

AC:

280

AN:

68016

Other (OTH)

AF:

0.00473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

125

156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00425

Hom.:

Bravo

AF:

0.00472

ExAC

AF:

0.00319

AC:

387

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.0080

(source)

DANN

Benign

0.62

DEOGEN2

Benign

0.0050

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0025

LIST_S2

Benign

0.0050

M_CAP

Benign

0.0021

MetaRNN

Benign

0.0048

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.80

PhyloP100

-1.8

PrimateAI

Uncertain

0.55

PROVEAN

Benign

1.4

REVEL

Benign

0.063

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.11

MVP

0.061

MPC

0.51

ClinPred

0.0017

GERP RS

-5.0

PromoterAI

-0.0068

Neutral

(source)

Varity_R

0.064

gMVP

0.12

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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