rs1324631593

Variant names:

• chr1-53211122-T-C
• rs1324631593
• NM_000098.3:c.1448T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000098.3(CPT2):​c.1448T>C​(p.Val483Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000028 in 1,461,724 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 (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 5.13
• Publications: 2 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)

ENSG00000236723 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 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, 5 uncertain in NM_000098.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4032653).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT2	NM_000098.3	c.1448T>C	p.Val483Ala	missense_variant	Exon 4 of 5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2	c.1448T>C	p.Val483Ala	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.1448T>C	p.Val483Ala	missense_variant	Exon 4 of 5	1	NM_000098.3	ENSP00000360541.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 250944 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461724 Hom.: 0 Cov.: 34 AF XY: 0.0000261 AC XY: 19 AN XY: 727148

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1111926

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.0000378

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Carnitine palmitoyltransferase II deficiency Uncertain:2

Jan 17, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 483 of the CPT2 protein (p.Val483Ala). 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 variant has not been reported in the literature in individuals affected with CPT2-related conditions. ClinVar contains an entry for this variant (Variation ID: 529861). 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. -

Carnitine palmitoyl transferase II deficiency, neonatal form Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 12, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carnitine palmitoyl transferase II deficiency, myopathic form Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Uncertain:1

Jan 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1448T>C (p.V483A) alteration is located in exon 4 (coding exon 4) of the CPT2 gene. This alteration results from a T to C substitution at nucleotide position 1448, causing the valine (V) at amino acid position 483 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

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

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

Aug 20, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Carnitine palmitoyl transferase II deficiency, severe infantile form Uncertain:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D;.;.;T;T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;T;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Uncertain	-0.078	T
MutationAssessor	Benign	1.2	L;.;.;.;.
PhyloP100		5.1
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;.;.;.;.
REVEL	Uncertain	0.63
Sift	Benign	0.14	T;.;.;.;.
Sift4G	Benign	0.18	T;.;.;.;.
Polyphen		0.29	B;.;.;.;.
Vest4		0.49
MVP		0.98
MPC		0.32
ClinPred		0.39	T
GERP RS		5.8
Varity_R		0.16
gMVP		0.56
Mutation Taster		=50/50

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: rs1324631593; hg19: chr1-53676794;