NM_001868.4:c.165G>C

Variant names:

• chr7-130381647-G-C
• rs1126899
• NM_001868.4:c.165G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001868.4(CPA1):​c.165G>C​(p.Gly55Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 1,612,906 control chromosomes in the GnomAD database, including 221,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G55G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.55 (23469 hom., cov: 32)
  • Exomes 𝑓: 0.52 (197873 hom.)
• Consequence: CPA1 NM_001868.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.02
• Publications: 21 publications found

Genes affected

CPA1 (HGNC:2296): (carboxypeptidase A1) This gene encodes a member of the carboxypeptidase A family of zinc metalloproteases. This enzyme is produced in the pancreas and preferentially cleaves C-terminal branched-chain and aromatic amino acids from dietary proteins. This gene and several family members are present in a gene cluster on chromosome 7. Mutations in this gene may be linked to chronic pancreatitis, while elevated protein levels may be associated with pancreatic cancer. [provided by RefSeq, Jan 2015]

CPA1 Gene-Disease associations (from GenCC):

• hereditary chronic pancreatitis

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-130381647-G-C is Benign according to our data. Variant chr7-130381647-G-C is described in ClinVar as Benign. ClinVar VariationId is 258474.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.638 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001868.4. 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
	CPA1	NM_001868.4	MANE Select	c.165G>C	p.Gly55Gly	synonymous	Exon 3 of 10	NP_001859.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA1	ENST00000011292.8	TSL:1 MANE Select	c.165G>C	p.Gly55Gly	synonymous	Exon 3 of 10	ENSP00000011292.3
	CPA1	ENST00000484324.1	TSL:5	c.-100G>C		5_prime_UTR	Exon 2 of 9	ENSP00000419497.1
	CPA1	ENST00000476062.5	TSL:5	c.-100G>C		5_prime_UTR	Exon 3 of 9	ENSP00000419408.1

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83821 AN: 151838 Hom.: 23454 Cov.: 32

Gnomad AFR AF: 0.644

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.604

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.502

Gnomad OTH AF: 0.526

GnomAD2 exomes AF: 0.536 AC: 133603 AN: 249372 AF XY: 0.528

Gnomad AFR exome AF: 0.653

Gnomad AMR exome AF: 0.591

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.587

Gnomad FIN exome AF: 0.528

Gnomad NFE exome AF: 0.506

Gnomad OTH exome AF: 0.533

GnomAD4 exome AF: 0.518 AC: 757217 AN: 1460950 Hom.: 197873 Cov.: 46 AF XY: 0.517 AC XY: 375687 AN XY: 726828

African (AFR) AF: 0.656 AC: 21956 AN: 33456

American (AMR) AF: 0.586 AC: 26223 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.552 AC: 14415 AN: 26118

East Asian (EAS) AF: 0.614 AC: 24368 AN: 39694

South Asian (SAS) AF: 0.491 AC: 42357 AN: 86232

European-Finnish (FIN) AF: 0.531 AC: 28240 AN: 53144

Middle Eastern (MID) AF: 0.518 AC: 2987 AN: 5766

European-Non Finnish (NFE) AF: 0.508 AC: 564923 AN: 1111460

Other (OTH) AF: 0.526 AC: 31748 AN: 60368

GnomAD4 genome AF: 0.552 AC: 83886 AN: 151956 Hom.: 23469 Cov.: 32 AF XY: 0.551 AC XY: 40894 AN XY: 74240

African (AFR) AF: 0.644 AC: 26709 AN: 41456

American (AMR) AF: 0.545 AC: 8324 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1951 AN: 3468

East Asian (EAS) AF: 0.604 AC: 3101 AN: 5138

South Asian (SAS) AF: 0.492 AC: 2371 AN: 4818

European-Finnish (FIN) AF: 0.523 AC: 5516 AN: 10552

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.502 AC: 34091 AN: 67926

Other (OTH) AF: 0.529 AC: 1118 AN: 2114

Alfa AF: 0.482 Hom.: 4977

Bravo AF: 0.559

Asia WGS AF: 0.553 AC: 1920 AN: 3478

EpiCase AF: 0.493

EpiControl AF: 0.506

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Hereditary pancreatitis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.5
DANN	Benign	0.66
PhyloP100		-1.0
Mutation Taster		=300/0	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: rs1126899; hg19: chr7-130021488; COSMIC: COSV50568158; COSMIC: COSV50568158;