16-75223193-A-G

Position:

• chr16-75223193-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001906.6(CTRB1):​c.289A>G​(p.Asn97Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 18)
• Consequence: CTRB1 NM_001906.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.40

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.052667707).
• BP6: Variant 16-75223193-A-G is Benign according to our data. Variant chr16-75223193-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 3078721.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CTRB1	NM_001906.6	c.289A>G	p.Asn97Asp	missense_variant	4/7	ENST00000361017.9	NP_001897.4
CTRB1	NM_001329190.2	c.289A>G	p.Asn97Asp	missense_variant	4/6		NP_001316119.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CTRB1	ENST00000361017.9	c.289A>G	p.Asn97Asp	missense_variant	4/7	1	NM_001906.6	ENSP00000354294.4
CTRB1	ENST00000495583.1	c.361A>G	p.Asn121Asp	missense_variant	3/4	2		ENSP00000463301.1

Frequencies

GnomAD3 genomes Cov.: 18

GnomAD4 exome Cov.: 14

GnomAD4 genome Cov.: 18

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 09, 2024

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.038
DANN	Benign	0.88
DEOGEN2	Benign	0.14	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0026	N
LIST_S2	Benign	0.045	T;T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.73	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.97	N;.
REVEL	Benign	0.22
Sift	Benign	1.0	T;.
Sift4G	Benign	0.83	T;T
Polyphen		0.0	B;.
Vest4		0.079
MutPred		0.49		Gain of ubiquitination at K102 (P = 0.0828);.;
MVP		0.30
MPC		2.1
ClinPred		0.063	T
GERP RS		-9.2
Varity_R		0.056
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-75257091;