rs74315294

Variant names:

• chr1-53202427-C-T
• rs74315294
• NM_000098.3:c.338C>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 15P and 1B. PS3 PM1 PP3 PP5_Very_Strong BS2_Supporting

The NM_000098.3(CPT2):​c.338C>T​(p.Ser113Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00167 in 1,611,988 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002503776: Homozygous cases are reported with significantly reduced CPT II enzyme activity and slightly reduced or normal long-chain fatty acid oxidation levels in tissues, and markedly reduced CPT II activity is also demonstrated in in vitro expression studies (PP4, PS3_Supporting" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S113S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (8 hom.)
• Consequence: CPT2 NM_000098.3 missense, splice_region
• Scores: Splicing: ADA: 0.9981
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:48 O:2
• Conservation: PhyloP100: 7.03
• Publications: 141 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: Myriad Women’s Health, ClinGen
• carnitine palmitoyl transferase II deficiency, neonatal form

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• carnitine palmitoyl transferase II deficiency, myopathic form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• carnitine palmitoyl transferase II deficiency, severe infantile form

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• encephalopathy, acute, infection-induced, susceptibility to, 4

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002503776: Homozygous cases are reported with significantly reduced CPT II enzyme activity and slightly reduced or normal long-chain fatty acid oxidation levels in tissues, and markedly reduced CPT II activity is also demonstrated in in vitro expression studies (PP4, PS3_Supporting; PMID: 8358442, 8651281).; SCV002570306: Experimental studies demonstrate that this missense variant significantly reduces enzyme activity.; SCV005045122: Functional studies show abnormal regulation of the enzyme and thermal instability, indicating that this variant impacts protein function (Taroni F et al., PMID: 8358442; Motlagh L et al., PMID: 26477380).; SCV000238785: Published functional studies demonstrate a damaging effect (PMID: 27123472, 8358442, 26477380); SCV003799713: Functional analyses of the variant protein shows a reduction in stability leading to decreased enzyme activity (Motlagh 2016a, Motlagh 2016b, Taroni 1993).; SCV000358097: Taroni et al. (1993) demonstrated that, when transiently expressed in COS-1 cells, the p.Ser113Leu variant displayed significantly reduced CPT II activity but similar enzyme synthesis compared to wild-type. PMID:8358442 Bonnefont et al. (1996) showed a reduction to 20% of wild-type of residual CPT II activity in fibroblasts from a patient homozygous for the p.Ser113Leu variant.; SCV000632605: Experimental studies have shown that this missense change affects CPT2 function (PMID: 2647738, 8358442, 27123472).; SCV000711454: Biochemical characterization and in vitro functional studies also provide evidence that the p.Ser113Leu variant may impact protein function (Taroni 1993, Bonnefont 1996).; SCV001142299: Functional analysis demonstrates that the c.338C>T variant is associated with a significant reduction in enzyme activity (PMID:8358442).; SCV003841325: Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 26477380, 27123472, 8358442).; SCV000741685: "COS1 cells with this variant demonstrated reduced activity compared to wild type (Taroni, 1993)."
• PM1: In a topological_domain Mitochondrial matrix (size 152) in uniprot entity CPT2_HUMAN there are 15 pathogenic changes around while only 4 benign (79%) in NM_000098.3
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 1-53202427-C-T is Pathogenic according to our data. Variant chr1-53202427-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 8953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 8 AR,Unknown geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT2	NM_000098.3	MANE Select	c.338C>T	p.Ser113Leu	missense splice_region	Exon 3 of 5	NP_000089.1	P23786
	CPT2	NM_001330589.2		c.338C>T	p.Ser113Leu	missense splice_region	Exon 3 of 5	NP_001317518.1	A0A1B0GTB8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT2	ENST00000371486.4	TSL:1 MANE Select	c.338C>T	p.Ser113Leu	missense splice_region	Exon 3 of 5	ENSP00000360541.3	P23786
	CPT2	ENST00000873097.1		c.338C>T	p.Ser113Leu	missense splice_region	Exon 3 of 6	ENSP00000543156.1
	CPT2	ENST00000637252.1	TSL:5	c.338C>T	p.Ser113Leu	missense splice_region	Exon 3 of 6	ENSP00000490492.1	A0A1B0GVF3

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 200 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00200

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00139 AC: 350 AN: 251450 AF XY: 0.00141

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00724

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00171 AC: 2496 AN: 1459714 Hom.: 8 Cov.: 29 AF XY: 0.00168 AC XY: 1221 AN XY: 726314

African (AFR) AF: 0.000299 AC: 10 AN: 33446

American (AMR) AF: 0.000894 AC: 40 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00923 AC: 241 AN: 26114

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39688

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86186

European-Finnish (FIN) AF: 0.000168 AC: 9 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00186 AC: 2061 AN: 1110048

Other (OTH) AF: 0.00159 AC: 96 AN: 60324

GnomAD4 genome AF: 0.00132 AC: 201 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74458

African (AFR) AF: 0.000361 AC: 15 AN: 41564

American (AMR) AF: 0.000523 AC: 8 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00922 AC: 32 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00200 AC: 136 AN: 68022

Other (OTH) AF: 0.00238 AC: 5 AN: 2104

Alfa AF: 0.00165 Hom.: 4

Bravo AF: 0.00135

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00127 AC: 154

EpiCase AF: 0.00224

EpiControl AF: 0.00219

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Carnitine palmitoyl transferase II deficiency, myopathic form (12)
11	-	-	not provided (11)
9	-	-	Carnitine palmitoyl transferase II deficiency, severe infantile form (9)
7	-	-	Carnitine palmitoyltransferase II deficiency (9)
2	-	-	Carnitine palmitoyl transferase II deficiency, neonatal form (2)
2	-	-	Encephalopathy, acute, infection-induced, susceptibility to, 4 (2)
1	-	-	Abnormality of the musculature (1)
1	-	-	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 (1)
1	-	-	Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Rhabdomyolysis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.041	T
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.0
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.85
MVP		1.0
MPC		0.51
ClinPred		0.50	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.62
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.020		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: rs74315294; hg19: chr1-53668099; COSMIC: COSV65186978;