Genetic Variant CTRB1:p.Asp145Asn (chr16-75223565-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001906.6(CTRB1):c.433G>A(p.Asp145Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00056 ( 0 hom., cov: 9)

Exomes 𝑓: 0.00055 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

CTRB1
NM_001906.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.664

Publications

0 publications found

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]

CTRB1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.020581007).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001906.6. 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
	CTRB1	NM_001906.6	MANE Select	c.433G>A	p.Asp145Asn	missense	Exon 5 of 7	NP_001897.4	P17538
	CTRB1	NM_001329190.2		c.433G>A	p.Asp145Asn	missense	Exon 5 of 6	NP_001316119.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTRB1	ENST00000361017.9	TSL:1 MANE Select	c.433G>A	p.Asp145Asn	missense	Exon 5 of 7	ENSP00000354294.4	P17538
	CTRB1	ENST00000495583.1	TSL:2	c.505G>A	p.Asp169Asn	missense	Exon 4 of 4	ENSP00000463301.1	J3QKZ2

Frequencies

GnomAD3 genomes

AF:

0.000549

AC:

AN:

67444

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000196

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00109

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000439

AC:

AN:

52404

AF XY:

0.000598

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000872

Gnomad OTH exome

AF:

0.000569

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000550

AC:

307

AN:

558428

Hom.:

Cov.:

AF XY:

0.000598

AC XY:

174

AN XY:

290820

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

16438

American (AMR)

AF:

0.000693

AC:

AN:

21650

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15000

East Asian (EAS)

AF:

0.00

AC:

AN:

30776

South Asian (SAS)

AF:

0.00

AC:

AN:

51640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37552

Middle Eastern (MID)

AF:

0.000431

AC:

AN:

2322

European-Non Finnish (NFE)

AF:

0.000800

AC:

283

AN:

353850

Other (OTH)

AF:

0.000274

AC:

AN:

29200

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.354

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000563

AC:

AN:

67538

Hom.:

Cov.:

AF XY:

0.000639

AC XY:

AN XY:

31282

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000196

AC:

AN:

20446

American (AMR)

AF:

0.00

AC:

AN:

5504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1984

East Asian (EAS)

AF:

0.00

AC:

AN:

1808

South Asian (SAS)

AF:

0.00

AC:

AN:

1606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4544

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.00112

AC:

AN:

30246

Other (OTH)

AF:

0.00

AC:

AN:

784

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.356

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:

0.000504

Hom.:

ExAC

AF:

0.0000697

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

0.078

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.45

CADD

Benign

1.4

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.15

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.18

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.021

MetaSVM

Benign

-0.74

PhyloP100

-0.66

PrimateAI

Benign

0.45

PROVEAN

Benign

1.3

REVEL

Benign

0.13

Sift

Benign

0.72

Sift4G

Benign

0.61

Polyphen

0.0010

Vest4

0.19

MVP

0.55

MPC

1.9

ClinPred

0.023

GERP RS

-2.2

Varity_R

0.048

gMVP

0.41

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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