3-42263639-C-G

Variant names:

• chr3-42263639-C-G
• rs754635
• NM_000729.6:c.-2-7G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000729.6(CCK):​c.-2-7G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.867 in 1,555,678 control chromosomes in the GnomAD database, including 587,738 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.82 (51712 hom., cov: 35)
  • Exomes 𝑓: 0.87 (536026 hom.)
• Consequence: CCK NM_000729.6 splice_region, intron
• Scores: Splicing: ADA: 0.00002282
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.288
• Publications: 20 publications found

Genes affected

CCK (HGNC:1569): (cholecystokinin) This gene encodes a member of the gastrin/cholecystokinin family of proteins. The encoded preproprotein is proteolytically processed to generate multiple protein products, including the peptide hormones cholecystokinin-8, -12, -33, and others. The encoded peptides have been shown to regulate gastric acid secretion and food intake. A sulfated form of cholecystokinin-8 may modulate neuronal activity in the brain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2015]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.883 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCK	NM_000729.6	c.-2-7G>C		splice_region_variant, intron_variant	Intron 3 of 4	ENST00000396169.7	NP_000720.1
CCK	NM_001174138.3	c.-2-7G>C		splice_region_variant, intron_variant	Intron 1 of 2		NP_001167609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCK	ENST00000396169.7	c.-2-7G>C		splice_region_variant, intron_variant	Intron 3 of 4	1	NM_000729.6	ENSP00000379472.2
CCK	ENST00000334681.9	c.-2-7G>C		splice_region_variant, intron_variant	Intron 1 of 2	1		ENSP00000335657.5
CCK	ENST00000434608.1	c.-2-7G>C		splice_region_variant, intron_variant	Intron 1 of 2	1		ENSP00000409124.1
CCK	ENST00000484359.1	n.70-7G>C		splice_region_variant, intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes AF: 0.818 AC: 124453 AN: 152180 Hom.: 51697 Cov.: 35

Gnomad AFR AF: 0.674

Gnomad AMI AF: 0.934

Gnomad AMR AF: 0.810

Gnomad ASJ AF: 0.937

Gnomad EAS AF: 0.710

Gnomad SAS AF: 0.862

Gnomad FIN AF: 0.915

Gnomad MID AF: 0.864

Gnomad NFE AF: 0.889

Gnomad OTH AF: 0.842

GnomAD2 exomes AF: 0.838 AC: 150564 AN: 179756 AF XY: 0.846

Gnomad AFR exome AF: 0.668

Gnomad AMR exome AF: 0.727

Gnomad ASJ exome AF: 0.943

Gnomad EAS exome AF: 0.709

Gnomad FIN exome AF: 0.913

Gnomad NFE exome AF: 0.885

Gnomad OTH exome AF: 0.867

GnomAD4 exome AF: 0.872 AC: 1224097 AN: 1403380 Hom.: 536026 Cov.: 61 AF XY: 0.874 AC XY: 604823 AN XY: 692406

African (AFR) AF: 0.670 AC: 21406 AN: 31946

American (AMR) AF: 0.736 AC: 26137 AN: 35494

Ashkenazi Jewish (ASJ) AF: 0.943 AC: 22185 AN: 23538

East Asian (EAS) AF: 0.707 AC: 26816 AN: 37926

South Asian (SAS) AF: 0.865 AC: 68134 AN: 78744

European-Finnish (FIN) AF: 0.905 AC: 45451 AN: 50212

Middle Eastern (MID) AF: 0.864 AC: 4214 AN: 4878

European-Non Finnish (NFE) AF: 0.886 AC: 959584 AN: 1082904

Other (OTH) AF: 0.869 AC: 50170 AN: 57738

GnomAD4 genome AF: 0.818 AC: 124516 AN: 152298 Hom.: 51712 Cov.: 35 AF XY: 0.819 AC XY: 61003 AN XY: 74486

African (AFR) AF: 0.674 AC: 27975 AN: 41536

American (AMR) AF: 0.809 AC: 12388 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.937 AC: 3254 AN: 3472

East Asian (EAS) AF: 0.710 AC: 3673 AN: 5172

South Asian (SAS) AF: 0.863 AC: 4171 AN: 4834

European-Finnish (FIN) AF: 0.915 AC: 9724 AN: 10626

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.889 AC: 60451 AN: 68032

Other (OTH) AF: 0.839 AC: 1772 AN: 2112

Alfa AF: 0.860 Hom.: 10005

Bravo AF: 0.798

Asia WGS AF: 0.778 AC: 2709 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.2
DANN	Benign	0.53
PhyloP100		-0.29
PromoterAI		-0.036	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.010
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: rs754635; hg19: chr3-42305131;