rs4711690

Variant names:

• chr6-41741200-C-G
• rs4711690
• NM_002630.4:c.648-590G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002630.4(PGC):​c.648-590G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,525,826 control chromosomes in the GnomAD database, including 21,628 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3220 hom., cov: 32)
  • Exomes 𝑓: 0.16 (18408 hom.)
• Consequence: PGC NM_002630.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.714
• Publications: 20 publications found

Genes affected

PGC (HGNC:8890): (progastricsin) This gene encodes an aspartic proteinase that belongs to the peptidase family A1. The encoded protein is a digestive enzyme that is produced in the stomach and constitutes a major component of the gastric mucosa. This protein is also secreted into the serum. This protein is synthesized as an inactive zymogen that includes a highly basic prosegment. This enzyme is converted into its active mature form at low pH by sequential cleavage of the prosegment that is carried out by the enzyme itself. Polymorphisms in this gene are associated with susceptibility to gastric cancers. Serum levels of this enzyme are used as a biomarker for certain gastric diseases including Helicobacter pylori related gastritis. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 1. [provided by RefSeq, Oct 2009]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005326152).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.257 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PGC	NM_002630.4	c.648-590G>C		intron_variant	Intron 5 of 8	ENST00000373025.7	NP_002621.1
PGC	NM_001166424.2	c.723G>C	p.Gln241His	missense_variant	Exon 7 of 7		NP_001159896.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PGC	ENST00000373025.7	c.648-590G>C		intron_variant	Intron 5 of 8	1	NM_002630.4	ENSP00000362116.3
PGC	ENST00000425343.6	c.723G>C	p.Gln241His	missense_variant	Exon 7 of 7	2		ENSP00000405094.2
PGC	ENST00000356667.8	c.411-590G>C		intron_variant	Intron 3 of 3	5		ENSP00000349094.4

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29668 AN: 151978 Hom.: 3217 Cov.: 32

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.238

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.152

Gnomad OTH AF: 0.196

GnomAD2 exomes AF: 0.192 AC: 26057 AN: 135412 AF XY: 0.185

Gnomad AFR exome AF: 0.258

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.231

Gnomad FIN exome AF: 0.115

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.193

GnomAD4 exome AF: 0.158 AC: 216833 AN: 1373730 Hom.: 18408 Cov.: 33 AF XY: 0.157 AC XY: 106027 AN XY: 676448

African (AFR) AF: 0.265 AC: 8291 AN: 31334

American (AMR) AF: 0.291 AC: 10177 AN: 34948

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 6737 AN: 24632

East Asian (EAS) AF: 0.269 AC: 9534 AN: 35442

South Asian (SAS) AF: 0.136 AC: 10664 AN: 78142

European-Finnish (FIN) AF: 0.122 AC: 4228 AN: 34792

Middle Eastern (MID) AF: 0.231 AC: 1307 AN: 5650

European-Non Finnish (NFE) AF: 0.145 AC: 155760 AN: 1071352

Other (OTH) AF: 0.176 AC: 10135 AN: 57438

GnomAD4 genome AF: 0.195 AC: 29712 AN: 152096 Hom.: 3220 Cov.: 32 AF XY: 0.195 AC XY: 14519 AN XY: 74360

African (AFR) AF: 0.260 AC: 10786 AN: 41472

American (AMR) AF: 0.263 AC: 4022 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 964 AN: 3472

East Asian (EAS) AF: 0.237 AC: 1225 AN: 5160

South Asian (SAS) AF: 0.140 AC: 674 AN: 4828

European-Finnish (FIN) AF: 0.112 AC: 1181 AN: 10588

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.152 AC: 10308 AN: 67990

Other (OTH) AF: 0.194 AC: 410 AN: 2116

Alfa AF: 0.187 Hom.: 541

Bravo AF: 0.211

TwinsUK AF: 0.141 AC: 521

ALSPAC AF: 0.145 AC: 560

ExAC AF: 0.145 AC: 3153

Asia WGS AF: 0.202 AC: 703 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	11
DANN	Benign	0.97
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0053	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.71
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.041
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.030	D
Vest4		0.011
MutPred		0.42		Loss of sheet (P = 0.0126);
ClinPred		0.0030	T
GERP RS		-2.5
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4711690; hg19: chr6-41708938; COSMIC: COSV62675952; COSMIC: COSV62675952;