chr16-75223215-C-A

Position:

• chr16-75223215-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_001906.6(CTRB1):​c.311C>A​(p.Ala104Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 19)
• Consequence: CTRB1 NM_001906.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.06

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTRB1	NM_001906.6	c.311C>A	p.Ala104Asp	missense_variant	4/7	ENST00000361017.9	NP_001897.4
CTRB1	NM_001329190.2	c.311C>A	p.Ala104Asp	missense_variant	4/6		NP_001316119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTRB1	ENST00000361017.9	c.311C>A	p.Ala104Asp	missense_variant	4/7	1	NM_001906.6	ENSP00000354294.4
CTRB1	ENST00000495583.1	c.383C>A	p.Ala128Asp	missense_variant	3/4	2		ENSP00000463301.1

Frequencies

GnomAD3 genomes Cov.: 19

GnomAD4 exome Cov.: 10

GnomAD4 genome Cov.: 19

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

Oct 12, 2021

The c.311C>A (p.A104D) alteration is located in exon 4 (coding exon 4) of the CTRB1 gene. This alteration results from a C to A substitution at nucleotide position 311, causing the alanine (A) at amino acid position 104 to be replaced by an aspartic acid (D). 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	0.22
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Uncertain	0.51	D;.
Eigen	Benign	-0.099
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.048	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Uncertain	-0.16	T
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;.
REVEL	Uncertain	0.46
Sift	Uncertain	0.014	D;.
Sift4G	Benign	0.070	T;T
Polyphen		0.81	P;.
Vest4		0.43
MutPred		0.60		Loss of methylation at K105 (P = 0.0571);.;
MVP		0.89
MPC		3.1
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.53
gMVP		0.66

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: rs2076707794; hg19: chr16-75257113;