chr11-6270090-G-T

Position:

• chr11-6270090-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_176875.4(CCKBR):​c.406G>T​(p.Val136Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000827 in 1,450,450 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CCKBR NM_176875.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3417186).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCKBR	NM_176875.4	c.406G>T	p.Val136Leu	missense_variant, splice_region_variant	3/5	ENST00000334619.7
CCKBR	NM_001363552.2	c.406G>T	p.Val136Leu	missense_variant, splice_region_variant	3/4
CCKBR	NM_001318029.2	c.154G>T	p.Val52Leu	missense_variant, splice_region_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCKBR	ENST00000334619.7	c.406G>T	p.Val136Leu	missense_variant, splice_region_variant	3/5	1	NM_176875.4	P1
CCKBR	ENST00000525462.1	c.406G>T	p.Val136Leu	missense_variant, splice_region_variant	3/4	1
CCKBR	ENST00000532715.5	c.154G>T	p.Val52Leu	missense_variant, splice_region_variant	2/4	3
CCKBR	ENST00000525014.1	c.*162G>T		3_prime_UTR_variant	2/2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000827 AC: 12 AN: 1450450 Hom.: 0 Cov.: 33 AF XY: 0.00000973 AC XY: 7 AN XY: 719516

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000815

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000285 Hom.: 0

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 02, 2023

The c.406G>T (p.V136L) alteration is located in exon 3 (coding exon 3) of the CCKBR gene. This alteration results from a G to T substitution at nucleotide position 406, causing the valine (V) at amino acid position 136 to be replaced by a leucine (L). 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	Benign	0.21
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.73	T;D;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	1.1	L;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.047	D;T;T
Sift4G	Benign	0.091	T;T;T
Polyphen		0.54	P;.;P
Vest4		0.53
MutPred		0.56		Loss of catalytic residue at V136 (P = 0.0677);.;Loss of catalytic residue at V136 (P = 0.0677);
MVP		0.83
MPC		0.57
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.23
gMVP		0.49

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

LitVar

Other links and lift over

dbSNP: rs1485181507; hg19: chr11-6291320;