Genetic Variant NM_001025200.4:c.616G>A (chr16-75204787-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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. 15/22 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

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.01

Publications

2 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016259223).

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025200.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTRB2	NM_001025200.4	MANE Select	c.616G>A	p.Val206Ile	missense	Exon 6 of 7	NP_001020371.3	Q6GPI1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CTRB2	ENST00000303037.13	TSL:1 MANE Select	c.616G>A	p.Val206Ile	missense	Exon 6 of 7	ENSP00000303963.8	Q6GPI1
CTRB2	ENST00000562387.1	TSL:3	c.364G>A	p.Val122Ile	missense	Exon 3 of 4	ENSP00000455207.1	H3BP92
CTRB2	ENST00000562106.5	TSL:3	c.345+10G>A		intron	N/A	ENSP00000454599.1	H3BMY1

Frequencies

GnomAD3 genomes

AF:

0.000638

AC:

AN:

139478

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000854

AC:

100

AN:

117062

AF XY:

0.00109

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 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.:

Cov.:

AF XY:

0.000649

AC XY:

408

AN XY:

628818

show subpopulations

African (AFR)

AF:

0.000846

AC:

AN:

29550

American (AMR)

AF:

0.000819

AC:

AN:

28090

Ashkenazi Jewish (ASJ)

AF:

0.00365

AC:

AN:

21342

East Asian (EAS)

AF:

0.00

AC:

AN:

34804

South Asian (SAS)

AF:

0.00125

AC:

AN:

72580

European-Finnish (FIN)

AF:

0.0000223

AC:

AN:

44882

Middle Eastern (MID)

AF:

0.00849

AC:

AN:

3768

European-Non Finnish (NFE)

AF:

0.000474

AC:

470

AN:

991066

Other (OTH)

AF:

0.00125

AC:

AN:

52862

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

111

148

185

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000645

AC:

AN:

139596

Hom.:

Cov.:

AF XY:

0.000647

AC XY:

AN XY:

67956

show subpopulations

African (AFR)

AF:

0.000101

AC:

AN:

39526

American (AMR)

AF:

0.00124

AC:

AN:

13750

Ashkenazi Jewish (ASJ)

AF:

0.00585

AC:

AN:

3248

East Asian (EAS)

AF:

0.00

AC:

AN:

4792

South Asian (SAS)

AF:

0.000229

AC:

AN:

4370

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9272

Middle Eastern (MID)

AF:

0.0142

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000681

AC:

AN:

61670

Other (OTH)

AF:

0.00159

AC:

AN:

1890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00165

Hom.:

ExAC

AF:

0.000361

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.27

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.76

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.72

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.56

PhyloP100

4.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.69

REVEL

Benign

0.29

Sift

Benign

0.24

Sift4G

Benign

0.28

Polyphen

0.0010

Vest4

0.15

MVP

0.51

MPC

0.089

ClinPred

0.029

GERP RS

2.2

Varity_R

0.11

gMVP

0.39

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over