11-6270133-T-C

Position:

• chr11-6270133-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_176875.4(CCKBR):​c.449T>C​(p.Leu150Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCKBR NM_176875.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCKBR	NM_176875.4	c.449T>C	p.Leu150Pro	missense_variant	3/5	ENST00000334619.7
CCKBR	NM_001363552.2	c.449T>C	p.Leu150Pro	missense_variant	3/4
CCKBR	NM_001318029.2	c.197T>C	p.Leu66Pro	missense_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCKBR	ENST00000334619.7	c.449T>C	p.Leu150Pro	missense_variant	3/5	1	NM_176875.4	P1
CCKBR	ENST00000525462.1	c.449T>C	p.Leu150Pro	missense_variant	3/4	1
CCKBR	ENST00000532715.5	c.197T>C	p.Leu66Pro	missense_variant	2/4	3
CCKBR	ENST00000525014.1	c.*205T>C		3_prime_UTR_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Feb 28, 2024

The c.449T>C (p.L150P) alteration is located in exon 3 (coding exon 3) of the CCKBR gene. This alteration results from a T to C substitution at nucleotide position 449, causing the leucine (L) at amino acid position 150 to be replaced by a proline (P). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	-0.067	T
MutationAssessor	Pathogenic	4.3	H;.;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-5.6	D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.74
MutPred		0.86		Loss of stability (P = 0.0175);.;Loss of stability (P = 0.0175);
MVP		0.90
MPC		1.4
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.98
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-6291363;