rs1439696164

Variant names:

• chr6-41740588-C-G
• rs1439696164
• NM_002630.4:c.670G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002630.4(PGC):​c.670G>C​(p.Ala224Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,450,030 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PGC NM_002630.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002630.4. 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
	PGC	NM_002630.4	MANE Select	c.670G>C	p.Ala224Pro	missense	Exon 6 of 9	NP_002621.1	P20142-1
	PGC	NM_001166424.2		c.*387G>C		downstream_gene	N/A	NP_001159896.1	P20142-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGC	ENST00000373025.7	TSL:1 MANE Select	c.670G>C	p.Ala224Pro	missense	Exon 6 of 9	ENSP00000362116.3	P20142-1
	PGC	ENST00000950079.1		c.718G>C	p.Ala240Pro	missense	Exon 7 of 10	ENSP00000620138.1
	PGC	ENST00000950080.1		c.670G>C	p.Ala224Pro	missense	Exon 6 of 9	ENSP00000620139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1450030 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721324

African (AFR) AF: 0.00 AC: 0 AN: 32714

American (AMR) AF: 0.00 AC: 0 AN: 42932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 38612

South Asian (SAS) AF: 0.00 AC: 0 AN: 84528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53308

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106668

Other (OTH) AF: 0.00 AC: 0 AN: 59872

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.027	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		3.2
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.80	N
REVEL	Benign	0.23
Sift	Benign	0.061	T
Sift4G	Benign	0.23	T
Polyphen		0.97	D
Vest4		0.41
MutPred		0.54		Gain of disorder (P = 0.0412)
MVP		0.64
MPC		0.60
ClinPred		0.50	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.78
Mutation Taster		=79/21	polymorphism

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: rs1439696164; hg19: chr6-41708326;