rs2269383

Variant names:

• chr22-50574346-C-T
• rs2269383
• NM_152246.3:c.959G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3 BP4_Strong BA1

The NM_152246.3(CPT1B):​c.959G>A​(p.Gly320Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,612,678 control chromosomes in the GnomAD database, including 862 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (207 hom., cov: 33)
  • Exomes 𝑓: 0.013 (655 hom.)
• Consequence: CPT1B NM_152246.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.86
• Publications: 18 publications found

Genes affected

CPT1B (HGNC:2329): (carnitine palmitoyltransferase 1B) The protein encoded by this gene, a member of the carnitine/choline acetyltransferase family, is the rate-controlling enzyme of the long-chain fatty acid beta-oxidation pathway in muscle mitochondria. This enzyme is required for the net transport of long-chain fatty acyl-CoAs from the cytoplasm into the mitochondria. Multiple transcript variants encoding different isoforms have been found for this gene, and read-through transcripts are expressed from the upstream locus that include exons from this gene. [provided by RefSeq, Jun 2009]

CHKB-CPT1B (HGNC:41998): (CHKB-CPT1B readthrough (NMD candidate)) The genes CHKB and CPT1B are adjacent on chromosome 22 and read-through transcripts are expressed that include exons from both loci. The read-through transcripts are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to express proteins. [provided by RefSeq, Jun 2009]

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when BayesDel_addAF, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034022331).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152246.3. 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
	CPT1B	NM_152246.3	MANE Select	c.959G>A	p.Gly320Asp	missense	Exon 9 of 20	NP_689452.1	Q92523-1
	CPT1B	NM_001145135.2		c.959G>A	p.Gly320Asp	missense	Exon 9 of 20	NP_001138607.1	Q92523-1
	CPT1B	NM_001145137.2		c.959G>A	p.Gly320Asp	missense	Exon 8 of 19	NP_001138609.1	Q92523-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1B	ENST00000312108.12	TSL:1 MANE Select	c.959G>A	p.Gly320Asp	missense	Exon 9 of 20	ENSP00000312189.8	Q92523-1
	CPT1B	ENST00000395650.6	TSL:1	c.959G>A	p.Gly320Asp	missense	Exon 9 of 19	ENSP00000379011.2	Q92523-1
	CPT1B	ENST00000405237.7	TSL:1	c.959G>A	p.Gly320Asp	missense	Exon 8 of 19	ENSP00000385486.3	Q92523-1

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5486 AN: 152130 Hom.: 207 Cov.: 33

Gnomad AFR AF: 0.0891

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0192

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.139

Gnomad SAS AF: 0.0310

Gnomad FIN AF: 0.0193

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0264 AC: 6465 AN: 245092 AF XY: 0.0248

Gnomad AFR exome AF: 0.0896

Gnomad AMR exome AF: 0.00918

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0131 AC: 19085 AN: 1460430 Hom.: 655 Cov.: 32 AF XY: 0.0134 AC XY: 9735 AN XY: 726410

African (AFR) AF: 0.0933 AC: 3119 AN: 33442

American (AMR) AF: 0.0102 AC: 454 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.00771 AC: 201 AN: 26072

East Asian (EAS) AF: 0.142 AC: 5613 AN: 39660

South Asian (SAS) AF: 0.0277 AC: 2385 AN: 86000

European-Finnish (FIN) AF: 0.0147 AC: 785 AN: 53304

Middle Eastern (MID) AF: 0.0207 AC: 119 AN: 5760

European-Non Finnish (NFE) AF: 0.00473 AC: 5258 AN: 1111396

Other (OTH) AF: 0.0191 AC: 1151 AN: 60340

GnomAD4 genome AF: 0.0361 AC: 5500 AN: 152248 Hom.: 207 Cov.: 33 AF XY: 0.0382 AC XY: 2846 AN XY: 74460

African (AFR) AF: 0.0891 AC: 3700 AN: 41514

American (AMR) AF: 0.0192 AC: 294 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.139 AC: 720 AN: 5164

South Asian (SAS) AF: 0.0313 AC: 151 AN: 4828

European-Finnish (FIN) AF: 0.0193 AC: 205 AN: 10622

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.00494 AC: 336 AN: 68022

Other (OTH) AF: 0.0255 AC: 54 AN: 2114

Alfa AF: 0.0187 Hom.: 205

Bravo AF: 0.0388

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.0872 AC: 384

ESP6500EA AF: 0.00616 AC: 53

ExAC AF: 0.0271 AC: 3290

Asia WGS AF: 0.0700 AC: 245 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	4.1	H
PhyloP100		7.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.33
ClinPred		0.086	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.84
Mutation Taster		=86/14	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs2269383; hg19: chr22-51012775; COSMIC: COSV56417163; COSMIC: COSV56417163;