rs754386565

Positions:

• chr1-53211088-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000098.3(CPT2):​c.1414C>T​(p.Gln472Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q472Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CPT2 NM_000098.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.91

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]

(HGNC:):

ACMG classification

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 1-53211088-C-T is Pathogenic according to our data. Variant chr1-53211088-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371750.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	c.1414C>T	p.Gln472Ter	stop_gained	4/5	ENST00000371486.4
CPT2	NM_001330589.2	c.1414C>T	p.Gln472Ter	stop_gained	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.1414C>T	p.Gln472Ter	stop_gained	4/5	1	NM_000098.3	P1
	ENST00000629810.1	n.286-679G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251036 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135738

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461808 Hom.: 0 Cov.: 34 AF XY: 0.00000550 AC XY: 4 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carnitine palmitoyl transferase II deficiency, severe infantile form Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 21, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Carnitine palmitoyl transferase II deficiency, myopathic form;C1833511:Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form;C3280160:Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Carnitine palmitoyl transferase II deficiency, neonatal form Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 21, 2016

- -

Carnitine palmitoyl transferase II deficiency, myopathic form Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jun 21, 2016

- -

Encephalopathy, acute, infection-induced, susceptibility to, 4 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 01, 2024

- -

Carnitine palmitoyltransferase II deficiency Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 04, 2023

This sequence change creates a premature translational stop signal (p.Gln472*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 371750). This premature translational stop signal has been observed in individual(s) with clinical features of CPT2-related conditions (Invitae). This variant is present in population databases (rs754386565, gnomAD 0.02%). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A
Vest4		0.94
GERP RS		5.8

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

LitVar

Other links and lift over

dbSNP: rs754386565; hg19: chr1-53676760;