chr1-53210174-G-A

Variant names:

• chr1-53210174-G-A
• rs144760921
• NM_000098.3:c.500G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM1 BP4_Moderate

The NM_000098.3(CPT2):​c.500G>A​(p.Arg167Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000273 in 1,614,064 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R167W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (0 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 4.76

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]

ENSG00000236723 (HGNC:):

ACMG classification

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

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000098.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.16217428).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT2	NM_000098.3	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 5		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4	c.500G>A	p.Arg167Gln	missense_variant	Exon 4 of 5	1	NM_000098.3	ENSP00000360541.3

Frequencies

GnomAD3 genomes AF: 0.000256 AC: 39 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 251478 AF XY: 0.000177

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000274 AC: 401 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.000261 AC XY: 190 AN XY: 727248

Gnomad4 AFR exome AF: 0.000269 AC: 9 AN: 33480

Gnomad4 AMR exome AF: 0.000470 AC: 21 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.000321 AC: 357 AN: 1112012

Gnomad4 Remaining exome AF: 0.000232 AC: 14 AN: 60396

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74400

Gnomad4 AFR AF: 0.000289 AC: 0.000289115 AN: 0.000289115

Gnomad4 AMR AF: 0.000393 AC: 0.000392773 AN: 0.000392773

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000323 AC: 0.000323482 AN: 0.000323482

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000287

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000198 AC: 24

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency Uncertain:3 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jul 07, 2023

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Arg167Gln variant in the CPT2 gene has been previously reported in a monogenic dyslipidemia cohort (Johansen et al., 2014). This variant has been identified in 21/35,436 Latino/Admixed American chromosomes (58/282,850 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 529857). The arginine at position 167 is evolutionarily conserved. Computational tools predict that the p.Arg167Gln variant is deleterious; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg167Gln variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2_Supporting; PP3] -

Mar 09, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:2

Jun 19, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4_strong, PM2 -

Oct 29, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign in association with a CPT2-related disorder to our knowledge; This variant is associated with the following publications: (PMID: 24503134, 29429925, 35460704) -

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 Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Mar 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500G>A (p.R167Q) alteration is located in exon 4 (coding exon 4) of the CPT2 gene. This alteration results from a G to A substitution at nucleotide position 500, causing the arginine (R) at amino acid position 167 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CPT2-related disorder Uncertain:1

Sep 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CPT2 c.500G>A variant is predicted to result in the amino acid substitution p.Arg167Gln. This variant was reported in individuals with hypercholesterolaemia without further evidence supporting pathogenicity (Johansen et al. 2014. PubMed ID: 24503134; Dong et al. 2022. PubMed ID: 35460704). This variant is reported in 0.059% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D;.;.;T;T
Eigen	Benign	0.055
Eigen_PC	Benign	0.037
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D;D;D;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.16	T;T;T;T;T
MetaSVM	Uncertain	0.087	D
MutationAssessor	Uncertain	2.6	M;.;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.5	N;.;.;.;.
REVEL	Uncertain	0.45
Sift	Benign	0.30	T;.;.;.;.
Sift4G	Benign	0.19	T;.;.;.;.
Polyphen		0.75	P;.;.;.;.
Vest4		0.29
MVP		1.0
MPC		0.20
ClinPred		0.18	T
GERP RS		3.7
Varity_R		0.37
gMVP		0.65
Mutation Taster		=65/35	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

Publications

LitVar

Other links and lift over

dbSNP: rs144760921; hg19: chr1-53675846;