chr16-75223173-A-G

Variant names:

• chr16-75223173-A-G
• rs1225332088
• NM_001906.6:c.269A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001906.6(CTRB1):​c.269A>G​(p.Asp90Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 17)
  • Exomes 𝑓: 0.000038 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTRB1 NM_001906.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.269A>G	p.Asp90Gly	missense	Exon 4 of 7	NP_001897.4	P17538
	CTRB1	NM_001329190.2		c.269A>G	p.Asp90Gly	missense	Exon 4 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.269A>G	p.Asp90Gly	missense	Exon 4 of 7	ENSP00000354294.4	P17538
	CTRB1	ENST00000495583.1	TSL:2	c.341A>G	p.Asp114Gly	missense	Exon 3 of 4	ENSP00000463301.1	J3QKZ2

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111990 Hom.: 0 Cov.: 17

Gnomad AFR AF: 0.0000321

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000998

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000379 AC: 39 AN: 1028810 Hom.: 0 Cov.: 15 AF XY: 0.0000327 AC XY: 17 AN XY: 520220

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

African (AFR) AF: 0.00 AC: 0 AN: 26876

American (AMR) AF: 0.00 AC: 0 AN: 32952

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22292

East Asian (EAS) AF: 0.00 AC: 0 AN: 33918

South Asian (SAS) AF: 0.00 AC: 0 AN: 72130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3616

European-Non Finnish (NFE) AF: 0.0000511 AC: 38 AN: 743060

Other (OTH) AF: 0.0000218 AC: 1 AN: 45790

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000566643), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000179 AC: 2 AN: 111990 Hom.: 0 Cov.: 17 AF XY: 0.00 AC XY: 0 AN XY: 52910

African (AFR) AF: 0.0000321 AC: 1 AN: 31110

American (AMR) AF: 0.0000998 AC: 1 AN: 10016

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2918

East Asian (EAS) AF: 0.00 AC: 0 AN: 3528

South Asian (SAS) AF: 0.00 AC: 0 AN: 3136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6046

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 252

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52860

Other (OTH) AF: 0.00 AC: 0 AN: 1416

Alfa AF: 0.0000843 Hom.: 0

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	0.57
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	0.70	D
PhyloP100		2.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.010	D
Sift4G	Benign	0.074	T
Polyphen		0.24	B
Vest4		0.28
MutPred		0.58		Loss of catalytic residue at D90 (P = 0.0959)
MVP		0.98
MPC		2.9
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.88
gMVP		0.73
Mutation Taster		=62/38	polymorphism

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: rs1225332088; hg19: chr16-75257071;