dbSNP rs515726173: CPT2:p.Leu178_Ile186delinsPhe (chr1-53210208-GAACCCTGCAAAAAGTGACACTATC-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM4PP3PP5

The NM_000098.3(CPT2):c.534_558delGAACCCTGCAAAAAGTGACACTATCinsT(p.Leu178_Ile186delinsPhe) variant causes a missense, conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L178L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CPT2
NM_000098.3 missense, conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1O:1

Conservation

PhyloP100: 7.57

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

carnitine palmitoyltransferase II deficiency
Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, ClinGen
carnitine palmitoyl transferase II deficiency, neonatal form
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
carnitine palmitoyl transferase II deficiency, myopathic form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
carnitine palmitoyl transferase II deficiency, severe infantile form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
encephalopathy, acute, infection-induced, susceptibility to, 4
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CPT2 links:

ENSG00000236723 (HGNC:):

ENSG00000236723 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a topological_domain Mitochondrial matrix (size 152) in uniprot entity CPT2_HUMAN there are 15 pathogenic changes around while only 4 benign (79%) in NM_000098.3

PM4

Nonframeshift variant in NON repetitive region in NM_000098.3.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 1-53210208-GAACCCTGCAAAAAGTGACACTATC-T is Pathogenic according to our data. Variant chr1-53210208-GAACCCTGCAAAAAGTGACACTATC-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 130885.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT2	NM_000098.3	MANE Select	c.534_558delGAACCCTGCAAAAAGTGACACTATCinsT	p.Leu178_Ile186delinsPhe	missense conservative_inframe_deletion	Exon 4 of 5	NP_000089.1	P23786
	CPT2	NM_001330589.2		c.534_558delGAACCCTGCAAAAAGTGACACTATCinsT	p.Leu178_Ile186delinsPhe	missense conservative_inframe_deletion	Exon 4 of 5	NP_001317518.1	A0A1B0GTB8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CPT2	ENST00000371486.4	TSL:1 MANE Select	c.534_558delGAACCCTGCAAAAAGTGACACTATCinsT	p.Leu178_Ile186delinsPhe	missense conservative_inframe_deletion	Exon 4 of 5	ENSP00000360541.3	P23786
CPT2	ENST00000873097.1		c.534_558delGAACCCTGCAAAAAGTGACACTATCinsT	p.Leu178_Ile186delinsPhe	missense conservative_inframe_deletion	Exon 4 of 6	ENSP00000543156.1
CPT2	ENST00000637252.1	TSL:5	c.534_558delGAACCCTGCAAAAAGTGACACTATCinsT	p.Leu178_Ile186delinsPhe	missense conservative_inframe_deletion	Exon 4 of 6	ENSP00000490492.1	A0A1B0GVF3

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Carnitine palmitoyl transferase II deficiency, neonatal form (1)

Carnitine palmitoyltransferase II deficiency (2)

CPT2-related disorder (1)

Encephalopathy, acute, infection-induced, susceptibility to, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.6

Splicing

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over