1-53210251-C-T

Position:

• chr1-53210251-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000098.3(CPT2):​c.577C>T​(p.Arg193Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000158 in 1,614,170 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R193H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2 B:4
• Conservation: PhyloP100: 3.66

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048920453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT2	NM_000098.3	c.577C>T	p.Arg193Cys	missense_variant	4/5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2	c.577C>T	p.Arg193Cys	missense_variant	4/5		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4	c.577C>T	p.Arg193Cys	missense_variant	4/5	1	NM_000098.3	ENSP00000360541.3

Frequencies

GnomAD3 genomes AF: 0.000269 AC: 41 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00327

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000366 AC: 92 AN: 251426 Hom.: 2 AF XY: 0.000419 AC XY: 57 AN XY: 135908

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00201

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000146 AC: 214 AN: 1461884 Hom.: 1 Cov.: 31 AF XY: 0.000176 AC XY: 128 AN XY: 727240

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000655

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000629

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74466

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00328

Gnomad4 SAS AF: 0.00187

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000954 Hom.: 0

Bravo AF: 0.000208

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000502 AC: 61

Asia WGS AF: 0.0100 AC: 35 AN: 3476

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:3 Uncertain:2

Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 22, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 25, 2020	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 25, 2022	Variant summary: CPT2 c.577C>T (p.Arg193Cys) results in a non-conservative amino acid change located in the Choline/carnitine acyltransferase domain (IPR039551) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 251426 control chromosomes, predominantly at a frequency of 0.002 within the East Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CPT2 causing Carnitine Palmitoyltransferase II Deficiency phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.577C>T in individuals affected with Carnitine Palmitoyltransferase II Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a predominant consensus as likely benign (n=3) (VUS, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 11, 2016	- -

Carnitine palmitoyltransferase II deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 14, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.0060	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D;.;.;T;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Benign	0.049	T;T;T;T;T
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.3	D;.;.;.;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0040	D;.;.;.;.
Sift4G	Uncertain	0.0020	D;.;.;.;.
Polyphen		1.0	D;.;.;.;.
Vest4		0.94
MVP		0.99
MPC		0.64
ClinPred		0.13	T
GERP RS		5.5
Varity_R		0.41
gMVP		0.72

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: rs375968699; hg19: chr1-53675923;