NM_001025200.4:c.616G>A

Variant names:

• chr16-75204787-C-T
• rs762909710
• NM_001025200.4:c.616G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.01

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]

ACMG classification

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
CTRB2	NM_001025200.4	c.616G>A	p.Val206Ile	missense_variant	Exon 6 of 7	ENST00000303037.13	NP_001020371.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTRB2	ENST00000303037.13	c.616G>A	p.Val206Ile	missense_variant	Exon 6 of 7	1	NM_001025200.4	ENSP00000303963.8

Frequencies

GnomAD3 genomes AF: 0.000638 AC: 89 AN: 139478 Hom.: 2 Cov.: 24

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

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

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

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

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

Other links and lift over

dbSNP: rs762909710; hg19: chr16-75238685;