16-75204799-C-G

Variant names:

• chr16-75204799-C-G
• rs1378576714
• NM_001025200.4:c.604G>C

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.604G>C​(p.Gly202Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000154 in 1,298,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CTRB2 NM_001025200.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.85
• 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, 0.992

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.604G>C	p.Gly202Arg	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.604G>C	p.Gly202Arg	missense	Exon 6 of 7	ENSP00000303963.8	Q6GPI1
	CTRB2	ENST00000562387.1	TSL:3	c.352G>C	p.Gly118Arg	missense	Exon 3 of 4	ENSP00000455207.1	H3BP92
	CTRB2	ENST00000562106.5	TSL:3	c.343G>C	p.Gly115Arg	missense splice_region	Exon 3 of 4	ENSP00000454599.1	H3BMY1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000154 AC: 2 AN: 1298214 Hom.: 0 Cov.: 23 AF XY: 0.00000157 AC XY: 1 AN XY: 638828

African (AFR) AF: 0.00 AC: 0 AN: 30316

American (AMR) AF: 0.00 AC: 0 AN: 32956

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23012

East Asian (EAS) AF: 0.00 AC: 0 AN: 35092

South Asian (SAS) AF: 0.0000133 AC: 1 AN: 75398

European-Finnish (FIN) AF: 0.0000215 AC: 1 AN: 46484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3888

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 997050

Other (OTH) AF: 0.00 AC: 0 AN: 54018

GnomAD4 genome Cov.: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		4.9
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.022	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.96		Gain of methylation at G202 (P = 0.0231)
MVP		0.92
MPC		0.50
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.67
gMVP		0.94

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

dbSNP: rs1378576714; hg19: chr16-75238697;