7-130380524-C-CGG

Variant names:

• chr7-130380524-C-CGG
• rs1796390308
• NM_001868.4:c.8_9dupGG

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PVS1_Strong PM2 BP6

The NM_001868.4(CPA1):​c.8_9dupGG​(p.Leu4GlyfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000228 in 1,314,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: CPA1 NM_001868.4 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.25
• Publications: 0 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 7-130380524-C-CGG is Benign according to our data. Variant chr7-130380524-C-CGG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1761610.

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.8_9dupGG	p.Leu4GlyfsTer5	frameshift	Exon 1 of 10	NP_001859.1	P15085

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPA1	ENST00000011292.8	TSL:1 MANE Select	c.8_9dupGG	p.Leu4GlyfsTer5	frameshift	Exon 1 of 10	ENSP00000011292.3	P15085
	CPA1	ENST00000604896.5	TSL:3	c.8_9dupGG	p.Leu4GlyfsTer5	frameshift	Exon 1 of 6	ENSP00000475021.2	S4R433
	CPA1	ENST00000481342.5	TSL:3	c.-200+119_-200+120dupGG		intron	N/A	ENSP00000420218.1	C9JQ63

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000172 AC: 2 AN: 1162508 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 556958

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

African (AFR) AF: 0.00 AC: 0 AN: 24952

American (AMR) AF: 0.000112 AC: 2 AN: 17830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15394

East Asian (EAS) AF: 0.00 AC: 0 AN: 30536

South Asian (SAS) AF: 0.00 AC: 0 AN: 26902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4630

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 955492

Other (OTH) AF: 0.00 AC: 0 AN: 46514

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152156 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.2
Mutation Taster		=24/176	disease causing (fs/PTC)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1796390308; hg19: chr7-130020365;