rs192275019

chr1-53210039-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM1 PM2 BP4_Strong

The NM_000098.3(CPT2):c.365C>T(p.Ser122Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000195 in 1,613,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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. S122S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 2.11

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 Uncertain_significance. Variant got 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 1 benign, 6 uncertain in NM_000098.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014732182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.365C>T	p.Ser122Phe	missense_variant	4/5	ENST00000371486.4
CPT2	NM_001330589.2	c.365C>T	p.Ser122Phe	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.365C>T	p.Ser122Phe	missense_variant	4/5	1	NM_000098.3	P1
	ENST00000629810.1	n.579G>A		non_coding_transcript_exon_variant	3/3	5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 151912 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00463

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000414 AC: 104 AN: 251266 Hom.: 0 AF XY: 0.000471 AC XY: 64 AN XY: 135904

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00348

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000194 AC: 284 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.000224 AC XY: 163 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00385

Gnomad4 SAS exome AF: 0.00125

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74326

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00464

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.000185

ExAC AF: 0.000461 AC: 56

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2022	Reported in a patient with acute necrotizing encephalopathy who also harbors a potentially disease-causing variant in the RANBP2 gene (Iyer et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 26010953, 32102593) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 13, 2016

- -

Carnitine palmitoyltransferase II deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.;.;T;T
Eigen	Benign	-0.058
Eigen_PC	Benign	0.023
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.7	M;.;.;.;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-3.1	D;.;.;.;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.025	D;.;.;.;.
Sift4G	Uncertain	0.038	D;.;.;.;.
Polyphen		0.018	B;.;.;.;.
Vest4		0.39
MVP		0.99
MPC		0.36
ClinPred		0.12	T
GERP RS		3.8
Varity_R		0.25
gMVP		0.42

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: rs192275019; hg19: chr1-53675711; COSMIC: COSV53759415; COSMIC: COSV53759415;