6-41742372-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002630.4(PGC):c.565G>A(p.Val189Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000328 in 1,614,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: PGC NM_002630.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.505

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.082698375).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGC	NM_002630.4	c.565G>A	p.Val189Met	missense_variant	5/9	ENST00000373025.7
PGC	NM_001166424.2	c.565G>A	p.Val189Met	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGC	ENST00000373025.7	c.565G>A	p.Val189Met	missense_variant	5/9	1	NM_002630.4	P1
PGC	ENST00000425343.6	c.565G>A	p.Val189Met	missense_variant	5/7	2
PGC	ENST00000356667.8	c.328G>A	p.Val110Met	missense_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251404 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135880

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727236

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74464

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.0000986 Hom.: 0

Bravo AF: 0.000193

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 15, 2021

The c.565G>A (p.V189M) alteration is located in exon 5 (coding exon 5) of the PGC gene. This alteration results from a G to A substitution at nucleotide position 565, causing the valine (V) at amino acid position 189 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	0.66
Dann	Benign	0.77
DEOGEN2	Benign	0.026	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.27	T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.083	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.19
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.10	T;.;T
Polyphen		0.017	B;.;.
Vest4		0.17
MVP		0.19
MPC		0.11
ClinPred		0.036	T
GERP RS		-8.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.037
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs372664007; hg19: chr6-41710110;