Variant rs754363068 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000098.3(CPT2):c.110_111dup(p.Ser38AlafsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,538,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q36Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CPT2
NM_000098.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 0.0970

Variant links:

Genes affected

CPT2 (HGNC:2330): (carnitine palmitoyltransferase 2) The protein encoded by this gene is a nuclear protein which is transported to the mitochondrial inner membrane. Together with carnitine palmitoyltransferase I, the encoded protein oxidizes long-chain fatty acids in the mitochondria. Defects in this gene are associated with mitochondrial long-chain fatty-acid (LCFA) oxidation disorders. [provided by RefSeq, Jul 2008]

CPT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-53197050-A-AGC is Pathogenic according to our data. Variant chr1-53197050-A-AGC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3 linkuse as main transcript	c.110_111dup	p.Ser38AlafsTer36	frameshift_variant	1/5	ENST00000371486.4
CPT2	NM_001330589.2 linkuse as main transcript	c.110_111dup	p.Ser38AlafsTer36	frameshift_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4 linkuse as main transcript	c.110_111dup	p.Ser38AlafsTer36	frameshift_variant	1/5	1	NM_000098.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152058

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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

GnomAD3 exomes

AF:

0.0000377

AC:

AN:

132500

Hom.:

AF XY:

0.0000277

AC XY:

AN XY:

72332

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000164

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000205

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1386844

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

684562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000196

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.0000346

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152058

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74272

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 07, 2021	Variant summary: CPT2 c.110_111dupGC (p.Ser38AlafsX36) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 3.3e-05 in 153476 control chromosomes. c.110_111dupGC has been reported in the literature in individuals affected with Carnitine Palmitoyltransferase II Deficiency and in the setting of carrier screening for recessive disorders (example, Bastin_2011, Martin_2000, Thuiller_2003, Lazarin_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 10%-<30% of normal muscle CPT residual enzyme activity in a compound heterozygous genotype (Martin_2000). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2024	This sequence change creates a premature translational stop signal (p.Ser38Alafs*36) in the CPT2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPT2 are known to be pathogenic (PMID: 16781677, 16996287). This variant is present in population databases (rs754363068, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with carnitine palmitoyltransferase II deficiency (PMID: 10862092, 12673791). ClinVar contains an entry for this variant (Variation ID: 371697). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Carnitine palmitoyl transferase II deficiency, neonatal form

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 27, 2015	- -

Carnitine palmitoyl transferase II deficiency, severe infantile form

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Dec 27, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Carnitine palmitoyl transferase II deficiency, myopathic form

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Dec 27, 2015

- -

Encephalopathy, acute, infection-induced, susceptibility to, 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 21, 2024

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 25, 2024

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Also denoted as 36-38 insGC due to alternate nomenclature; This variant is associated with the following publications: (PMID: 22975760, 31589614, 12673791, 10862092) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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