NM_000730.3:c.1093G>A

Variant names:

• chr4-26481832-C-T
• rs52795588
• NM_000730.3:c.1093G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000730.3(CCKAR):​c.1093G>A​(p.Val365Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00124 in 1,613,510 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (9 hom.)
• Consequence: CCKAR NM_000730.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 6.08
• Publications: 7 publications found

Genes affected

CCKAR (HGNC:1570): (cholecystokinin A receptor) This gene encodes a G-protein coupled receptor that binds non-sulfated members of the cholecystokinin (CCK) family of peptide hormones. This receptor is a major physiologic mediator of pancreatic enzyme secretion and smooth muscle contraction of the gallbladder and stomach. In the central and peripheral nervous system this receptor regulates satiety and the release of beta-endorphin and dopamine. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017394722).
• BP6: Variant 4-26481832-C-T is Benign according to our data. Variant chr4-26481832-C-T is described in ClinVar as Benign. ClinVar VariationId is 17530.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00698 (1063/152292) while in subpopulation AFR AF = 0.0236 (979/41560). AF 95% confidence interval is 0.0223. There are 12 homozygotes in GnomAd4. There are 482 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000730.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCKAR	NM_000730.3	MANE Select	c.1093G>A	p.Val365Ile	missense	Exon 5 of 5	NP_000721.1	P32238

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCKAR	ENST00000295589.4	TSL:1 MANE Select	c.1093G>A	p.Val365Ile	missense	Exon 5 of 5	ENSP00000295589.3	P32238

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 1061 AN: 152174 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00175 AC: 438 AN: 250544 AF XY: 0.00137

Gnomad AFR exome AF: 0.0241

Gnomad AMR exome AF: 0.000840

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000642 AC: 938 AN: 1461218 Hom.: 9 Cov.: 32 AF XY: 0.000561 AC XY: 408 AN XY: 726856

African (AFR) AF: 0.0219 AC: 734 AN: 33462

American (AMR) AF: 0.00121 AC: 54 AN: 44672

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26048

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111686

Other (OTH) AF: 0.00147 AC: 89 AN: 60360

GnomAD4 genome AF: 0.00698 AC: 1063 AN: 152292 Hom.: 12 Cov.: 32 AF XY: 0.00647 AC XY: 482 AN XY: 74460

African (AFR) AF: 0.0236 AC: 979 AN: 41560

American (AMR) AF: 0.00438 AC: 67 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00223 Hom.: 15

Bravo AF: 0.00779

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00233 AC: 283

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CHOLECYSTOKININ A RECEPTOR POLYMORPHISM (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.23
Sift	Benign	0.031	D
Sift4G	Benign	0.10	T
Polyphen		1.0	D
Vest4		0.59
MVP		0.44
MPC		0.62
ClinPred		0.015	T
GERP RS		5.3
Varity_R		0.21
gMVP		0.61
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs52795588; hg19: chr4-26483454; COSMIC: COSV55162221;