rs148035648

Positions:

• chr1-53210027-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 3P and 10B. PM1 PP3 BP4_Strong BP6 BS1 BS2_Supporting

The NM_000098.3(CPT2):​c.353A>G​(p.Asp118Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,613,310 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D118D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00044 (6 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 8.95

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000098.3
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.015848875).
• BP6: Variant 1-53210027-A-G is Benign according to our data. Variant chr1-53210027-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 203666.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000439 (641/1461524) while in subpopulation AMR AF= 0.0138 (618/44722). AF 95% confidence interval is 0.0129. There are 6 homozygotes in gnomad4_exome. There are 248 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.353A>G	p.Asp118Gly	missense_variant	4/5	ENST00000371486.4
CPT2	NM_001330589.2	c.353A>G	p.Asp118Gly	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.353A>G	p.Asp118Gly	missense_variant	4/5	1	NM_000098.3	P1
	ENST00000629810.1	n.591T>C		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.000837 AC: 127 AN: 151668 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000291

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00728

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: 0.0000294

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.00203 AC: 508 AN: 250816 Hom.: 5 AF XY: 0.00144 AC XY: 195 AN XY: 135834

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.0143

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: 0.00000880

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000439 AC: 641 AN: 1461524 Hom.: 6 Cov.: 31 AF XY: 0.000341 AC XY: 248 AN XY: 727114

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0138

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: 0.00000540

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000837 AC: 127 AN: 151786 Hom.: 0 Cov.: 32 AF XY: 0.000850 AC XY: 63 AN XY: 74158

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.00727

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.000154 Hom.: 0

Bravo AF: 0.00150

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 30, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	The CPT2 c.353A>G; p.Asp118Gly variant (rs148035648), to our knowledge, is not reported in the medical literature but is reported as uncertain significance/benign in ClinVar (Variation ID: 203666). This variant is found in the Latino population with an overall allele frequency of 1.5% (505/34418 alleles, including 5 homozygotes) in the Genome Aggregation Database. The aspartic acid at codon 118 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Splicing analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site. However, given the lack of clinical and functional data, the significance of the p.Asp118Gly variant is uncertain at this time. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 10, 2021

- -

CPT2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Carnitine palmitoyltransferase II deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;.;.;T;T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
MetaRNN	Benign	0.016	T;T;T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.2	D;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0040	D;.;.;.;.
Sift4G	Uncertain	0.0050	D;.;.;.;.
Polyphen		0.98	D;.;.;.;.
Vest4		0.88
MVP		1.0
MPC		0.58
ClinPred		0.17	T
GERP RS		5.7
Varity_R		0.95
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148035648; hg19: chr1-53675699; COSMIC: COSV104589800; COSMIC: COSV104589800;