NM_001025200.4:c.616G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001025200.4(CTRB2):​c.616G>A​(p.Val206Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000618 in 1,418,540 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00064 ( 2 hom., cov: 24)
Exomes 𝑓: 0.00061 ( 38 hom. )

Consequence

CTRB2
NM_001025200.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.016259223).
BS2
High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CTRB2NM_001025200.4 linkc.616G>A p.Val206Ile 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
CTRB2ENST00000303037.13 linkc.616G>A p.Val206Ile missense_variant Exon 6 of 7 1 NM_001025200.4 ENSP00000303963.8 Q6GPI1

Frequencies

GnomAD3 genomes
AF:
0.000638
AC:
89
AN:
139478
Hom.:
2
Cov.:
24
show subpopulations
Gnomad AFR
AF:
0.0000761
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00124
Gnomad ASJ
AF:
0.00585
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000229
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0132
Gnomad NFE
AF:
0.000681
Gnomad OTH
AF:
0.00161
GnomAD3 exomes
AF:
0.000854
AC:
100
AN:
117062
Hom.:
7
AF XY:
0.00109
AC XY:
68
AN XY:
62538
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000853
Gnomad ASJ exome
AF:
0.00279
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00116
Gnomad FIN exome
AF:
0.0000793
Gnomad NFE exome
AF:
0.00104
Gnomad OTH exome
AF:
0.000910
GnomAD4 exome
AF:
0.000615
AC:
786
AN:
1278944
Hom.:
38
Cov.:
24
AF XY:
0.000649
AC XY:
408
AN XY:
628818
show subpopulations
Gnomad4 AFR exome
AF:
0.000846
Gnomad4 AMR exome
AF:
0.000819
Gnomad4 ASJ exome
AF:
0.00365
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00125
Gnomad4 FIN exome
AF:
0.0000223
Gnomad4 NFE exome
AF:
0.000474
Gnomad4 OTH exome
AF:
0.00125
GnomAD4 genome
AF:
0.000645
AC:
90
AN:
139596
Hom.:
2
Cov.:
24
AF XY:
0.000647
AC XY:
44
AN XY:
67956
show subpopulations
Gnomad4 AFR
AF:
0.000101
Gnomad4 AMR
AF:
0.00124
Gnomad4 ASJ
AF:
0.00585
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000229
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000681
Gnomad4 OTH
AF:
0.00159
Alfa
AF:
0.00165
Hom.:
4
ExAC
AF:
0.000361
AC:
26

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 17, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.616G>A (p.V206I) 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 616, causing the valine (V) at amino acid position 206 to be replaced by an isoleucine (I). 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
0.085
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
17
DANN
Benign
0.90
DEOGEN2
Benign
0.27
T;.
Eigen
Benign
-0.86
Eigen_PC
Benign
-0.76
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.72
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.016
T;T
MetaSVM
Benign
-0.66
T
MutationAssessor
Benign
0.56
N;.
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.69
N;N
REVEL
Benign
0.29
Sift
Benign
0.24
T;T
Sift4G
Benign
0.28
T;T
Polyphen
0.0010
B;.
Vest4
0.15
MVP
0.51
MPC
0.089
ClinPred
0.029
T
GERP RS
2.2
Varity_R
0.11
gMVP
0.39

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: rs762909710; hg19: chr16-75238685; API