22-50577409-T-C

Variant names:

• chr22-50577409-T-C
• rs3213445
• NM_152246.3:c.196A>G

Variant summary

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

The NM_152246.3(CPT1B):​c.196A>G​(p.Ile66Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0758 in 1,613,858 control chromosomes in the GnomAD database, including 8,204 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.093 (1060 hom., cov: 33)
  • Exomes 𝑓: 0.074 (7144 hom.)
• Consequence: CPT1B NM_152246.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21
• Publications: 39 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003050536).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.384 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1B	NM_152246.3	MANE Select	c.196A>G	p.Ile66Val	missense	Exon 3 of 20	NP_689452.1
	CPT1B	NM_001145135.2		c.196A>G	p.Ile66Val	missense	Exon 3 of 20	NP_001138607.1
	CPT1B	NM_001145137.2		c.196A>G	p.Ile66Val	missense	Exon 2 of 19	NP_001138609.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1B	ENST00000312108.12	TSL:1 MANE Select	c.196A>G	p.Ile66Val	missense	Exon 3 of 20	ENSP00000312189.8
	CPT1B	ENST00000395650.6	TSL:1	c.196A>G	p.Ile66Val	missense	Exon 3 of 19	ENSP00000379011.2
	CPT1B	ENST00000405237.7	TSL:1	c.196A>G	p.Ile66Val	missense	Exon 2 of 19	ENSP00000385486.3

Frequencies

GnomAD3 genomes AF: 0.0932 AC: 14182 AN: 152190 Hom.: 1057 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.397

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0525

Gnomad OTH AF: 0.0770

GnomAD2 exomes AF: 0.118 AC: 29350 AN: 248614 AF XY: 0.113

Gnomad AFR exome AF: 0.118

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.0498

Gnomad EAS exome AF: 0.424

Gnomad FIN exome AF: 0.0710

Gnomad NFE exome AF: 0.0523

Gnomad OTH exome AF: 0.0870

GnomAD4 exome AF: 0.0739 AC: 108053 AN: 1461550 Hom.: 7144 Cov.: 33 AF XY: 0.0754 AC XY: 54787 AN XY: 727064

African (AFR) AF: 0.117 AC: 3931 AN: 33480

American (AMR) AF: 0.190 AC: 8496 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0509 AC: 1331 AN: 26128

East Asian (EAS) AF: 0.382 AC: 15159 AN: 39700

South Asian (SAS) AF: 0.139 AC: 12021 AN: 86256

European-Finnish (FIN) AF: 0.0687 AC: 3651 AN: 53158

Middle Eastern (MID) AF: 0.0551 AC: 318 AN: 5768

European-Non Finnish (NFE) AF: 0.0522 AC: 58042 AN: 1111966

Other (OTH) AF: 0.0845 AC: 5104 AN: 60382

GnomAD4 genome AF: 0.0933 AC: 14216 AN: 152308 Hom.: 1060 Cov.: 33 AF XY: 0.0982 AC XY: 7315 AN XY: 74462

African (AFR) AF: 0.115 AC: 4793 AN: 41584

American (AMR) AF: 0.125 AC: 1910 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3472

East Asian (EAS) AF: 0.398 AC: 2057 AN: 5170

South Asian (SAS) AF: 0.158 AC: 764 AN: 4826

European-Finnish (FIN) AF: 0.0712 AC: 756 AN: 10620

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0525 AC: 3573 AN: 68018

Other (OTH) AF: 0.0795 AC: 168 AN: 2112

Alfa AF: 0.0692 Hom.: 2367

Bravo AF: 0.0992

TwinsUK AF: 0.0507 AC: 188

ALSPAC AF: 0.0573 AC: 221

ESP6500AA AF: 0.112 AC: 494

ESP6500EA AF: 0.0558 AC: 480

ExAC AF: 0.114 AC: 13787

Asia WGS AF: 0.253 AC: 880 AN: 3478

EpiCase AF: 0.0522

EpiControl AF: 0.0523

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	4.3
DANN	Benign	0.71
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	N
PhyloP100		2.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.18
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.030
ClinPred		0.0024	T
GERP RS		0.88
Varity_R		0.023
gMVP		0.57
Mutation Taster		=99/1	polymorphism (auto)

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: rs3213445; hg19: chr22-51015838; COSMIC: COSV56415750; COSMIC: COSV56415750;