NM_000098.3:c.34C>T

Variant names:

• chr1-53196977-C-T
• rs1270720547
• NM_000098.3:c.34C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000098.3(CPT2):​c.34C>T​(p.Arg12Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,234 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.101
• Publications: 0 publications found

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: ClinGen, Myriad Women’s Health
• carnitine palmitoyl transferase II deficiency, myopathic form

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• carnitine palmitoyl transferase II deficiency, neonatal form

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), PanelApp Australia
• carnitine palmitoyl transferase II deficiency, severe infantile form

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet
• encephalopathy, acute, infection-induced, susceptibility to, 4

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2199853).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT2	NM_000098.3	c.34C>T	p.Arg12Trp	missense_variant	Exon 1 of 5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2	c.34C>T	p.Arg12Trp	missense_variant	Exon 1 of 5		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4	c.34C>T	p.Arg12Trp	missense_variant	Exon 1 of 5	1	NM_000098.3	ENSP00000360541.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375234 Hom.: 0 Cov.: 30 AF XY: 0.00000147 AC XY: 1 AN XY: 678836

African (AFR) AF: 0.00 AC: 0 AN: 29310

American (AMR) AF: 0.00 AC: 0 AN: 35320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24648

East Asian (EAS) AF: 0.00 AC: 0 AN: 34340

South Asian (SAS) AF: 0.00 AC: 0 AN: 78378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4596

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1075730

Other (OTH) AF: 0.00 AC: 0 AN: 57184

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency Uncertain:1

Sep 05, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with tryptophan at codon 12 of the CPT2 protein (p.Arg12Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with CPT2-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CPT2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;T;T;T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.81	T;T;T;T;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.22	T;T;T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.
PhyloP100		0.10
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.2	N;.;.;.;.;.
REVEL	Benign	0.23
Sift	Uncertain	0.028	D;.;.;.;.;.
Sift4G	Uncertain	0.013	D;.;.;.;.;.
Polyphen		0.0010	B;.;.;.;.;.
Vest4		0.13
MutPred		0.40		Loss of disorder (P = 0.0042);Loss of disorder (P = 0.0042);Loss of disorder (P = 0.0042);Loss of disorder (P = 0.0042);Loss of disorder (P = 0.0042);Loss of disorder (P = 0.0042);
MVP		0.93
MPC		0.35
ClinPred		0.86	D
GERP RS		3.2
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.084
gMVP		0.68
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs1270720547; hg19: chr1-53662649;