16-75206185-C-T

Position:

• chr16-75206185-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001025200.4(CTRB2):​c.61G>A​(p.Val21Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTRB2 NM_001025200.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.839

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14564386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTRB2	NM_001025200.4	c.61G>A	p.Val21Ile	missense_variant	2/7	ENST00000303037.13	NP_001020371.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTRB2	ENST00000303037.13	c.61G>A	p.Val21Ile	missense_variant	2/7	1	NM_001025200.4	ENSP00000303963.8
CTRB2	ENST00000481611.1	n.975G>A		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1404670 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 693376

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2023

The c.61G>A (p.V21I) alteration is located in exon 2 (coding exon 2) of the CTRB2 gene. This alteration results from a G to A substitution at nucleotide position 61, causing the valine (V) at amino acid position 21 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	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.93	D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.27
Sift	Benign	0.17	T
Sift4G	Benign	0.12	T
Polyphen		0.014	B
Vest4		0.18
MutPred		0.43		Loss of catalytic residue at V21 (P = 0.1125);
MVP		0.62
MPC		0.080
ClinPred		0.21	T
GERP RS		4.5
Varity_R		0.055
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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

Other links and lift over

dbSNP: rs2038888909; hg19: chr16-75240083;