Genetic Variant CTRB2:p.Gly202Arg (chr16-75204799-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_001025200.4(CTRB2):c.604G>A(p.Gly202Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000104 in 1,438,926 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000010 ( 3 hom. )

Consequence

CTRB2
NM_001025200.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.85

Variant links:

Genes affected

CTRB2 (HGNC:2522): (chymotrypsinogen B2) This gene encodes a member of the serine protease family of enzymes and forms a principal precursor of the pancreatic proteolytic enzymes. The encoded preproprotein is synthesized in the acinar cells of the pancreas and secreted into the small intestine where it undergoes proteolytic activation to generate a functional enzyme. This CTRB2 gene is located head-to-head with the related CTRB1 gene. Some human populations have an alternate haplotype which inverts a 16.6 Kb region containing portions of intron 1, exon 1, and the upstream sequence of the CTRB1 and CTRB2 genes. In this inversion haplotype exon 1 and flanking sequence is swapped in CTRB1 and CTRB2. This inversion is associated with differential gene expression and increased risk for chronic pancreatitis. The GRCh38 assembly represents the minor allele for SNP rs8048956 of the CTRB1 gene. SNP rs8048956 is diagnostic for this inversion. [provided by RefSeq, Jan 2021]

CTRB2 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTRB2	NM_001025200.4 link	c.604G>A	p.Gly202Arg	missense_variant	Exon 6 of 7	ENST00000303037.13	NP_001020371.3	Q6GPI1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTRB2	ENST00000303037.13 link	c.604G>A	p.Gly202Arg	missense_variant	Exon 6 of 7	1	NM_001025200.4	ENSP00000303963.8		Q6GPI1

Frequencies

GnomAD3 genomes

AF:

0.0000142

AC:

AN:

140598

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000318

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000300

AC:

AN:

133294

Hom.:

AF XY:

0.0000282

AC XY:

AN XY:

70976

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000979

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000417

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000100

AC:

AN:

1298210

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

638828

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000285

Gnomad4 SAS exome

AF:

0.0000398

Gnomad4 FIN exome

AF:

0.0000215

Gnomad4 NFE exome

AF:

0.00000702

Gnomad4 OTH exome

AF:

0.0000185

GnomAD4 genome

AF:

0.0000142

AC:

AN:

140716

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

68302

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000318

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.604G>A (p.G202R) alteration is located in exon 6 (coding exon 6) of the CTRB2 gene. This alteration results from a G to A substitution at nucleotide position 604, causing the glycine (G) at amino acid position 202 to be replaced by an arginine (R). 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

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.36

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

D;T;D

M_CAP

Pathogenic

0.64

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.1

M;.;.

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Pathogenic

0.85

Sift

Uncertain

0.022

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.71

MutPred

0.96

Gain of methylation at G202 (P = 0.0231);.;.;

MVP

0.92

MPC

0.50

ClinPred

0.98

GERP RS

4.0

Varity_R

0.67

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over