Genetic Variant CPT1C:p.Arg514Leu (chr19-49708814-G-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001199753.2(CPT1C):c.1541G>T(p.Arg514Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000961 in 1,613,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R514Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000086 ( 0 hom. )

Consequence

CPT1C
NM_001199753.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 3.03

Publications

8 publications found

Variant links:

Genes affected

CPT1C (HGNC:18540): (carnitine palmitoyltransferase 1C) This gene encodes a member of the carnitine/choline acetyltransferase family. The encoded protein regulates the beta-oxidation and transport of long-chain fatty acids into mitochondria, and may play a role in the regulation of feeding behavior and whole-body energy homeostasis. Alternatively spliced transcript variants encoding multiple protein isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

CPT1C Gene-Disease associations (from GenCC):

hereditary spastic paraplegia 73
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
hereditary spastic paraplegia
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

CPT1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.024702221).

BP6

Variant 19-49708814-G-T is Benign according to our data. Variant chr19-49708814-G-T is described in ClinVar as Benign. ClinVar VariationId is 1164294.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000191 (29/152004) while in subpopulation EAS AF = 0.00542 (28/5166). AF 95% confidence interval is 0.00385. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High AC in GnomAd4 at 29 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199753.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CPT1C	NM_001199753.2	MANE Select	c.1541G>T	p.Arg514Leu	missense	Exon 14 of 20	NP_001186682.1
CPT1C	NM_001378482.1		c.1607G>T	p.Arg536Leu	missense	Exon 13 of 19	NP_001365411.1
CPT1C	NM_001199752.3		c.1541G>T	p.Arg514Leu	missense	Exon 14 of 20	NP_001186681.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CPT1C	ENST00000598293.6	TSL:2 MANE Select	c.1541G>T	p.Arg514Leu	missense	Exon 14 of 20	ENSP00000473028.1
CPT1C	ENST00000323446.9	TSL:1	c.1541G>T	p.Arg514Leu	missense	Exon 13 of 19	ENSP00000319343.4
CPT1C	ENST00000405931.6	TSL:1	c.1508G>T	p.Arg503Leu	missense	Exon 14 of 20	ENSP00000384465.2

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

151886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00541

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000478

AC:

120

AN:

250992

AF XY:

0.000413

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00626

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000862

AC:

126

AN:

1461022

Hom.:

Cov.:

AF XY:

0.0000812

AC XY:

AN XY:

726894

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00260

AC:

103

AN:

39686

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53270

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111404

Other (OTH)

AF:

0.000298

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000191

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00542

AC:

AN:

5166

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67962

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00000909

Hom.:

Bravo

AF:

0.000230

ExAC

AF:

0.000387

AC:

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CPT1C-related disorder

Benign:1

Jun 29, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Hereditary spastic paraplegia 73

Benign:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.025

MetaSVM

Uncertain

0.71

MutationAssessor

Uncertain

2.2

PhyloP100

3.0

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.65

MVP

0.94

MPC

1.4

ClinPred

0.11

GERP RS

4.4

Varity_R

0.50

gMVP

0.76

Mutation Taster

=86/14

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over