11-6259936-T-G

Variant names:

• chr11-6259936-T-G
• NM_176875.4:c.8T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_176875.4(CCKBR):​c.8T>G​(p.Leu3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000764 in 1,308,938 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: CCKBR NM_176875.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCKBR	NM_176875.4	c.8T>G	p.Leu3Arg	missense_variant	Exon 1 of 5	ENST00000334619.7	NP_795344.1
CCKBR	NM_001363552.2	c.8T>G	p.Leu3Arg	missense_variant	Exon 1 of 4		NP_001350481.1
CCKBR	NM_001318029.2	c.8T>G	p.Leu3Arg	missense_variant	Exon 1 of 4		NP_001304958.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCKBR	ENST00000334619.7	c.8T>G	p.Leu3Arg	missense_variant	Exon 1 of 5	1	NM_176875.4	ENSP00000335544.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.64e-7 AC: 1 AN: 1308938 Hom.: 0 Cov.: 33 AF XY: 0.00000156 AC XY: 1 AN XY: 642368

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000614

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8T>G (p.L3R) alteration is located in exon 1 (coding exon 1) of the CCKBR gene. This alteration results from a T to G substitution at nucleotide position 8, causing the leucine (L) at amino acid position 3 to be replaced by an arginine (R). 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	0.11
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.;.;.;.
Eigen	Benign	-0.0071
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Pathogenic	0.29	D
MetaRNN	Uncertain	0.52	D;D;D;D;D
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.90	L;.;.;.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.85	N;N;N;D;N
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;D;D;D;D
Sift4G	Uncertain	0.016	D;D;D;D;D
Polyphen		1.0	D;.;.;.;D
Vest4		0.59
MutPred		0.22		Gain of MoRF binding (P = 0.0087);Gain of MoRF binding (P = 0.0087);Gain of MoRF binding (P = 0.0087);Gain of MoRF binding (P = 0.0087);Gain of MoRF binding (P = 0.0087);
MVP		0.88
MPC		0.61
ClinPred		0.50	T
GERP RS		0.18
Varity_R		0.32
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr11-6281166;