16-75222813-G-A

Variant summary

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

The NM_001906.6(CTRB1):​c.98G>A​(p.Arg33Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 26)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CTRB1
NM_001906.6 missense

Scores

2
6
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.07
Variant links:
Genes affected
CTRB1 (HGNC:2521): (chymotrypsinogen B1) 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 CTRB1 gene is located head-to-head with the related CTRB2 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 in intron 1 of the CTRB2 gene is diagnostic for this inversion. This CTRB1 gene encodes distinct isoforms, some or all of which may undergo similar processing to generate the mature protein. [provided by RefSeq, Jan 2021]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CTRB1NM_001906.6 linkuse as main transcriptc.98G>A p.Arg33Lys missense_variant 2/7 ENST00000361017.9 NP_001897.4 P17538
CTRB1NM_001329190.2 linkuse as main transcriptc.98G>A p.Arg33Lys missense_variant 2/6 NP_001316119.1 P17538

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CTRB1ENST00000361017.9 linkuse as main transcriptc.98G>A p.Arg33Lys missense_variant 2/71 NM_001906.6 ENSP00000354294.4 P17538
CTRB1ENST00000495583.1 linkuse as main transcriptc.170G>A p.Arg57Lys missense_variant 1/42 ENSP00000463301.1 J3QKZ2

Frequencies

GnomAD3 genomes
Cov.:
26
GnomAD3 exomes
AF:
0.0000127
AC:
2
AN:
157730
Hom.:
0
AF XY:
0.0000239
AC XY:
2
AN XY:
83542
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000171
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000143
AC:
2
AN:
1397262
Hom.:
0
Cov.:
31
AF XY:
0.00000290
AC XY:
2
AN XY:
688564
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000278
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000173
GnomAD4 genome
Cov.:
26

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsAug 08, 2023The c.98G>A (p.R33K) alteration is located in exon 2 (coding exon 2) of the CTRB1 gene. This alteration results from a G to A substitution at nucleotide position 98, causing the arginine (R) at amino acid position 33 to be replaced by a lysine (K). 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
0.30
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
21
DANN
Benign
0.81
DEOGEN2
Benign
0.15
T;.
Eigen
Benign
-0.29
Eigen_PC
Benign
-0.23
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.74
T;T
M_CAP
Pathogenic
0.43
D
MetaRNN
Uncertain
0.64
D;D
MetaSVM
Uncertain
0.24
D
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-2.3
N;.
REVEL
Uncertain
0.53
Sift
Benign
0.080
T;.
Sift4G
Benign
0.085
T;D
Polyphen
0.051
B;.
Vest4
0.29
MutPred
0.70
Loss of sheet (P = 0.1398);.;
MVP
0.87
MPC
0.080
ClinPred
0.57
D
GERP RS
3.4
Varity_R
0.32
gMVP
0.71

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

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

Other links and lift over

dbSNP: rs1460273237; hg19: chr16-75256711; API