Genetic Variant CCKBR:p.Pro41Thr (chr11-6260049-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_176875.4(CCKBR):c.121C>A(p.Pro41Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,443,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P41S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CCKBR
NM_176875.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.67

Publications

0 publications found

Variant links:

Genes affected

CCKBR (HGNC:1571): (cholecystokinin B receptor) This gene encodes a G-protein coupled receptor for gastrin and cholecystokinin (CCK), regulatory peptides of the brain and gastrointestinal tract. This protein is a type B gastrin receptor, which has a high affinity for both sulfated and nonsulfated CCK analogs and is found principally in the central nervous system and the gastrointestinal tract. Alternative splicing results in multiple transcript variants. A misspliced transcript variant including an intron has been observed in cells from colorectal and pancreatic tumors. [provided by RefSeq, Dec 2015]

CCKBR links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04441309).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_176875.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCKBR	NM_176875.4	MANE Select	c.121C>A	p.Pro41Thr	missense	Exon 1 of 5	NP_795344.1	P32239-1
CCKBR	NM_001363552.2		c.121C>A	p.Pro41Thr	missense	Exon 1 of 4	NP_001350481.1	P32239-2
CCKBR	NM_001318029.2		c.121C>A	p.Pro41Thr	missense	Exon 1 of 4	NP_001304958.1	E9PIC8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCKBR	ENST00000334619.7	TSL:1 MANE Select	c.121C>A	p.Pro41Thr	missense	Exon 1 of 5	ENSP00000335544.2	P32239-1
CCKBR	ENST00000525462.1	TSL:1	c.121C>A	p.Pro41Thr	missense	Exon 1 of 4	ENSP00000435534.1	P32239-2
CCKBR	ENST00000912313.1		c.121C>A	p.Pro41Thr	missense	Exon 1 of 5	ENSP00000582372.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000277

AC:

AN:

1443254

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

718014

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31912

American (AMR)

AF:

0.00

AC:

AN:

43162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25610

East Asian (EAS)

AF:

0.00

AC:

AN:

37644

South Asian (SAS)

AF:

0.00

AC:

AN:

84394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49976

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1105090

Other (OTH)

AF:

0.0000167

AC:

AN:

59762

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

7.3

(source)

DANN

Benign

0.34

DEOGEN2

Benign

0.061

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.69

M_CAP

Benign

0.018

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

-1.7

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.26

REVEL

Benign

0.032

Sift

Benign

0.90

Sift4G

Benign

0.64

Polyphen

0.0

Vest4

0.078

MutPred

0.38

Gain of phosphorylation at P41 (P = 0.0322)

MVP

0.56

MPC

0.38

ClinPred

0.036

GERP RS

-2.1

PromoterAI

0.015

Neutral

(source)

Varity_R

0.059

gMVP

0.58

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over