rs201508063

Variant names:

• chr1-53211112-G-A
• rs201508063
• NM_000098.3:c.1438G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PP3_Moderate

The NM_000098.3(CPT2):​c.1438G>A​(p.Gly480Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000626 in 1,614,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (1 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:15
• Conservation: PhyloP100: 5.87
• Publications: 6 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)

ENSG00000236723 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000098.3
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.896

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.1438G>A	p.Gly480Arg	missense	Exon 4 of 5	NP_000089.1	P23786
	CPT2	NM_001330589.2		c.1438G>A	p.Gly480Arg	missense	Exon 4 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.1438G>A	p.Gly480Arg	missense	Exon 4 of 5	ENSP00000360541.3	P23786
	CPT2	ENST00000873097.1		c.1438G>A	p.Gly480Arg	missense	Exon 4 of 6	ENSP00000543156.1
	CPT2	ENST00000637252.1	TSL:5	c.1438G>A	p.Gly480Arg	missense	Exon 4 of 6	ENSP00000490492.1	A0A1B0GVF3

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000353

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000195 AC: 49 AN: 250908 AF XY: 0.000236

Gnomad AFR exome AF: 0.0000616

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: 0.000423

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000672 AC: 982 AN: 1461738 Hom.: 1 Cov.: 34 AF XY: 0.000660 AC XY: 480 AN XY: 727154

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

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

European-Non Finnish (NFE) AF: 0.000861 AC: 957 AN: 1111950

Other (OTH) AF: 0.000331 AC: 20 AN: 60390

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74466

African (AFR) AF: 0.0000962 AC: 4 AN: 41570

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000392 Hom.: 2

Bravo AF: 0.000295

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00104 AC: 4

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.000327

EpiControl AF: 0.000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Carnitine palmitoyltransferase II deficiency (3)
-	2	-	Carnitine palmitoyl transferase II deficiency, myopathic form (2)
-	2	-	Carnitine palmitoyl transferase II deficiency, severe infantile form (2)
-	2	-	not provided (2)
-	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 (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, neonatal form (1)
-	1	-	Encephalopathy, acute, infection-induced, susceptibility to, 4 (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		5.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.94		Gain of solvent accessibility (P = 0.0306)
MVP		0.99
MPC		0.60
ClinPred		0.84	D
GERP RS		5.8
Varity_R		0.78
gMVP		0.68
Mutation Taster		=24/76	disease causing

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: rs201508063; hg19: chr1-53676784; COSMIC: COSV53758582; COSMIC: COSV53758582;