16-75204809-C-T

Variant names:

• chr16-75204809-C-T
• NM_001025200.4:c.594G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001025200.4(CTRB2):​c.594G>A​(p.Met198Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000772 in 1,295,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: CTRB2 NM_001025200.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.69
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

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.594G>A	p.Met198Ile	missense	Exon 6 of 7	NP_001020371.3	Q6GPI1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CTRB2	ENST00000303037.13	TSL:1 MANE Select	c.594G>A	p.Met198Ile	missense	Exon 6 of 7	ENSP00000303963.8	Q6GPI1
	CTRB2	ENST00000562106.5	TSL:3	c.333G>A	p.Met111Ile	missense	Exon 3 of 4	ENSP00000454599.1	H3BMY1
	CTRB2	ENST00000562387.1	TSL:3	c.342G>A	p.Met114Ile	missense	Exon 3 of 4	ENSP00000455207.1	H3BP92

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 7.72e-7 AC: 1 AN: 1295810 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 638046

African (AFR) AF: 0.00 AC: 0 AN: 30276

American (AMR) AF: 0.00 AC: 0 AN: 33584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23244

East Asian (EAS) AF: 0.00 AC: 0 AN: 35086

South Asian (SAS) AF: 0.00 AC: 0 AN: 75776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46836

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3908

European-Non Finnish (NFE) AF: 0.00000101 AC: 1 AN: 993058

Other (OTH) AF: 0.00 AC: 0 AN: 54042

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.97	D
Vest4		0.79
MutPred		0.85		Loss of MoRF binding (P = 0.0882)
MVP		0.95
MPC		0.23
ClinPred		0.92	D
GERP RS		4.2
Varity_R		0.89
gMVP		0.76

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

Other links and lift over

hg19: chr16-75238707;