16-75205774-C-T

Variant names:

• chr16-75205774-C-T
• rs901293366
• NM_001025200.4:c.283G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001025200.4(CTRB2):​c.283G>A​(p.Glu95Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 9)
  • Exomes 𝑓: 0.000074 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CTRB2 NM_001025200.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.470
• Publications: 1 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_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21943313).

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.283G>A	p.Glu95Lys	missense	Exon 4 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.283G>A	p.Glu95Lys	missense	Exon 4 of 7	ENSP00000303963.8	Q6GPI1
	CTRB2	ENST00000562106.5	TSL:3	c.22G>A	p.Glu8Lys	missense	Exon 1 of 4	ENSP00000454599.1	H3BMY1
	CTRB2	ENST00000562387.1	TSL:3	c.31G>A	p.Glu11Lys	missense	Exon 1 of 4	ENSP00000455207.1	H3BP92

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 3 AN: 76082 Hom.: 0 Cov.: 9

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000720

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000904 AC: 8 AN: 88464 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000736 AC: 58 AN: 788460 Hom.: 0 Cov.: 11 AF XY: 0.0000892 AC XY: 36 AN XY: 403754

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

African (AFR) AF: 0.000247 AC: 4 AN: 16200

American (AMR) AF: 0.00 AC: 0 AN: 30766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18018

East Asian (EAS) AF: 0.00 AC: 0 AN: 32628

South Asian (SAS) AF: 0.000303 AC: 18 AN: 59446

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43908

Middle Eastern (MID) AF: 0.000788 AC: 2 AN: 2538

European-Non Finnish (NFE) AF: 0.0000602 AC: 33 AN: 548232

Other (OTH) AF: 0.0000272 AC: 1 AN: 36724

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000000710543), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000394 AC: 3 AN: 76082 Hom.: 0 Cov.: 9 AF XY: 0.0000286 AC XY: 1 AN XY: 34960

African (AFR) AF: 0.00 AC: 0 AN: 14424

American (AMR) AF: 0.00 AC: 0 AN: 8268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2002

East Asian (EAS) AF: 0.00 AC: 0 AN: 2934

South Asian (SAS) AF: 0.00 AC: 0 AN: 1874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 172

European-Non Finnish (NFE) AF: 0.0000720 AC: 3 AN: 41662

Other (OTH) AF: 0.00 AC: 0 AN: 1042

Alfa AF: 0.000148 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	Benign	0.12
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.17	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.47
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.85	N
REVEL	Uncertain	0.31
Sift	Benign	0.63	T
Sift4G	Benign	0.45	T
Polyphen		0.71	P
Vest4		0.12
MutPred		0.57		Gain of ubiquitination at E95 (P = 0.0104)
MVP		0.91
MPC		0.12
ClinPred		0.036	T
GERP RS		1.1
PromoterAI		-0.019	Neutral
Varity_R		0.10
gMVP		0.39
Mutation Taster		=90/10	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: rs901293366; hg19: chr16-75239672;