chr11-6270654-T-C

Position:

• chr11-6270654-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.662T>C​(p.Leu221Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,456,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CCKBR NM_176875.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.21

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, 0.845

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCKBR	NM_176875.4	c.662T>C	p.Leu221Pro	missense_variant	4/5	ENST00000334619.7
CCKBR	NM_001363552.2	c.662T>C	p.Leu221Pro	missense_variant	4/4
CCKBR	NM_001318029.2	c.410T>C	p.Leu137Pro	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCKBR	ENST00000334619.7	c.662T>C	p.Leu221Pro	missense_variant	4/5	1	NM_176875.4	P1
CCKBR	ENST00000525462.1	c.662T>C	p.Leu221Pro	missense_variant	4/4	1
CCKBR	ENST00000532715.5	c.410T>C	p.Leu137Pro	missense_variant	3/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456102 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723298

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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 27, 2021

The c.662T>C (p.L221P) alteration is located in exon 4 (coding exon 4) of the CCKBR gene. This alteration results from a T to C substitution at nucleotide position 662, causing the leucine (L) at amino acid position 221 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	0.76
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Benign	0.055	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.1	M;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-4.3	D;D;D
REVEL	Benign	0.28
Sift	Benign	0.060	T;D;D
Sift4G	Uncertain	0.052	T;D;D
Polyphen		0.99	D;.;D
Vest4		0.88
MutPred		0.78		Gain of catalytic residue at L221 (P = 0.0123);.;Gain of catalytic residue at L221 (P = 0.0123);
MVP		0.87
MPC		1.4
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.90
gMVP		0.95

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

LitVar

Other links and lift over

dbSNP: rs1309695318; hg19: chr11-6291884;