16-75222788-C-A

Position:

• chr16-75222788-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001906.6(CTRB1):​c.73C>A​(p.His25Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000707 in 1,555,640 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000061 (1 hom.)
• Consequence: CTRB1 NM_001906.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.128

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.022264957).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTRB1	NM_001906.6	c.73C>A	p.His25Asn	missense_variant	2/7	ENST00000361017.9	NP_001897.4
CTRB1	NM_001329190.2	c.73C>A	p.His25Asn	missense_variant	2/6		NP_001316119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTRB1	ENST00000361017.9	c.73C>A	p.His25Asn	missense_variant	2/7	1	NM_001906.6	ENSP00000354294.4
CTRB1	ENST00000495583.1	c.145C>A	p.His49Asn	missense_variant	1/4	2		ENSP00000463301.1

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152168 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000127 AC: 21 AN: 164852 Hom.: 1 AF XY: 0.000126 AC XY: 11 AN XY: 87626

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000396

Gnomad ASJ exome AF: 0.000590

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000761

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000613 AC: 86 AN: 1403354 Hom.: 1 Cov.: 31 AF XY: 0.0000650 AC XY: 45 AN XY: 692484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000415

Gnomad4 ASJ exome AF: 0.000518

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000407

Gnomad4 OTH exome AF: 0.000224

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152286 Hom.: 0 Cov.: 26 AF XY: 0.000161 AC XY: 12 AN XY: 74464

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000196

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000696 AC: 8

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

Jan 23, 2023

The c.73C>A (p.H25N) alteration is located in exon 2 (coding exon 2) of the CTRB1 gene. This alteration results from a C to A substitution at nucleotide position 73, causing the histidine (H) at amino acid position 25 to be replaced by an asparagine (N). 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	0.092
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	2.8
DANN	Benign	0.50
DEOGEN2	Benign	0.050	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.061	N
LIST_S2	Benign	0.32	T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Benign	-0.76	T
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.19	N;.
REVEL	Benign	0.14
Sift	Benign	0.27	T;.
Sift4G	Benign	0.44	T;T
Polyphen		0.0	B;.
Vest4		0.35
MVP		0.32
MPC		0.015
ClinPred		0.032	T
GERP RS		-2.8
Varity_R		0.044
gMVP		0.18

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: rs369201413; hg19: chr16-75256686;