rs1196469539

chr1-53197042-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000098.3(CPT2):c.99G>C(p.Gln33His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,538,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.806

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Mitochondrial matrix (size 152) in uniprot entity CPT2_HUMAN there are 20 pathogenic changes around while only 5 benign (80%) in NM_000098.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1517624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.99G>C	p.Gln33His	missense_variant	1/5	ENST00000371486.4
CPT2	NM_001330589.2	c.99G>C	p.Gln33His	missense_variant	1/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.99G>C	p.Gln33His	missense_variant	1/5	1	NM_000098.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000760 AC: 1 AN: 131544 Hom.: 0 AF XY: 0.0000139 AC XY: 1 AN XY: 71890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.0000208

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000195 AC: 27 AN: 1386444 Hom.: 0 Cov.: 30 AF XY: 0.0000161 AC XY: 11 AN XY: 684328

Gnomad4 AFR exome AF: 0.0000318

Gnomad4 AMR exome AF: 0.00

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: 0.0000223

Gnomad4 OTH exome AF: 0.0000346

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152084 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74276

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Carnitine palmitoyl transferase II deficiency, neonatal form Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Carnitine palmitoyl transferase II deficiency, myopathic form Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Carnitine palmitoyltransferase II deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 18, 2022

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 33 of the CPT2 protein (p.Gln33His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with CPT2-related conditions (PMID: 22494076). ClinVar contains an entry for this variant (Variation ID: 555897). 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	0.15
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T;.;.;T;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.78	T;T;T;T;T;T
M_CAP	Benign	0.083	D
MetaRNN	Benign	0.15	T;T;T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.
MutationTaster	Benign	0.98	N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;.;.;.;.;.
REVEL	Benign	0.15
Sift	Benign	0.083	T;.;.;.;.;.
Sift4G	Benign	0.095	T;.;.;.;.;.
Polyphen		0.012	B;.;.;.;.;.
Vest4		0.12
MutPred		0.20		Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);Gain of glycosylation at S38 (P = 0.121);
MVP		0.96
MPC		0.11
ClinPred		0.30	T
GERP RS		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.10
gMVP		0.38

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: rs1196469539; hg19: chr1-53662714;