Genetic Variant CPT1C:p.Glu197* (chr19-49701530-G-T) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_001199753.2(CPT1C):c.589G>T(p.Glu197*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,611,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CPT1C
NM_001199753.2 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.92

Publications

1 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
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: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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	UniProt
CPT1C	NM_001199753.2	MANE Select	c.589G>T	p.Glu197*	stop_gained	Exon 7 of 20	NP_001186682.1	Q8TCG5-1
CPT1C	NM_001378482.1		c.589G>T	p.Glu197*	stop_gained	Exon 7 of 19	NP_001365411.1
CPT1C	NM_001199752.3		c.589G>T	p.Glu197*	stop_gained	Exon 7 of 20	NP_001186681.1	Q8TCG5-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPT1C	ENST00000598293.6	TSL:2 MANE Select	c.589G>T	p.Glu197*	stop_gained	Exon 7 of 20	ENSP00000473028.1	Q8TCG5-1
CPT1C	ENST00000323446.9	TSL:1	c.589G>T	p.Glu197*	stop_gained	Exon 6 of 19	ENSP00000319343.4	Q8TCG5-1
CPT1C	ENST00000405931.6	TSL:1	c.589G>T	p.Glu197*	stop_gained	Exon 7 of 20	ENSP00000384465.2	Q8TCG5-2

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151914

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000805

AC:

AN:

248446

AF XY:

0.00000743

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000896

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1459972

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726152

show subpopulations

African (AFR)

AF:

0.0000599

AC:

AN:

33372

American (AMR)

AF:

0.00

AC:

AN:

44636

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26088

East Asian (EAS)

AF:

0.00

AC:

AN:

39606

South Asian (SAS)

AF:

0.00

AC:

AN:

86118

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110806

Other (OTH)

AF:

0.00

AC:

AN:

60292

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

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:

0.0000197

AC:

AN:

151914

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74206

show subpopulations

African (AFR)

AF:

0.0000726

AC:

AN:

41348

American (AMR)

AF:

0.00

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67982

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.51

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.88

PhyloP100

1.9

Vest4

0.86

GERP RS

3.3

Mutation Taster

=21/179

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.34

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.34

Position offset: 3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over