rs1799822

Variant names:

• chr1-53213557-A-G
• rs1799822
• NM_000098.3:c.1939A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000098.3(CPT2):​c.1939A>G​(p.Met647Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.195 in 1,613,856 control chromosomes in the GnomAD database, including 33,516 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M647I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2188 hom., cov: 33)
  • Exomes 𝑓: 0.20 (31328 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 7.43
• Publications: 52 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017347932).
• BP6: Variant 1-53213557-A-G is Benign according to our data. Variant chr1-53213557-A-G is described in ClinVar as Benign. ClinVar VariationId is 92433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

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.1939A>G	p.Met647Val	missense	Exon 5 of 5	NP_000089.1	P23786
	CPT2	NM_001330589.2		c.1870A>G	p.Met624Val	missense	Exon 5 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.1939A>G	p.Met647Val	missense	Exon 5 of 5	ENSP00000360541.3	P23786
	CPT2	ENST00000873097.1		c.2005A>G	p.Met669Val	missense	Exon 6 of 6	ENSP00000543156.1
	CPT2	ENST00000637252.1	TSL:5	c.1975A>G	p.Met659Val	missense	Exon 6 of 6	ENSP00000490492.1	A0A1B0GVF3

Frequencies

GnomAD3 genomes AF: 0.152 AC: 23057 AN: 152170 Hom.: 2187 Cov.: 33

Gnomad AFR AF: 0.0513

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.164

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.0817

Gnomad SAS AF: 0.0948

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.217

Gnomad OTH AF: 0.187

GnomAD2 exomes AF: 0.164 AC: 41251 AN: 250846 AF XY: 0.169

Gnomad AFR exome AF: 0.0460

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.0839

Gnomad FIN exome AF: 0.134

Gnomad NFE exome AF: 0.220

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.200 AC: 292279 AN: 1461568 Hom.: 31328 Cov.: 33 AF XY: 0.198 AC XY: 144011 AN XY: 727110

African (AFR) AF: 0.0440 AC: 1472 AN: 33476

American (AMR) AF: 0.130 AC: 5820 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6679 AN: 26136

East Asian (EAS) AF: 0.0669 AC: 2656 AN: 39700

South Asian (SAS) AF: 0.103 AC: 8879 AN: 86252

European-Finnish (FIN) AF: 0.134 AC: 7143 AN: 53416

Middle Eastern (MID) AF: 0.172 AC: 974 AN: 5668

European-Non Finnish (NFE) AF: 0.222 AC: 246784 AN: 1111814

Other (OTH) AF: 0.197 AC: 11872 AN: 60388

GnomAD4 genome AF: 0.152 AC: 23074 AN: 152288 Hom.: 2188 Cov.: 33 AF XY: 0.145 AC XY: 10783 AN XY: 74478

African (AFR) AF: 0.0515 AC: 2139 AN: 41562

American (AMR) AF: 0.163 AC: 2499 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 872 AN: 3470

East Asian (EAS) AF: 0.0821 AC: 426 AN: 5188

South Asian (SAS) AF: 0.0943 AC: 455 AN: 4826

European-Finnish (FIN) AF: 0.122 AC: 1299 AN: 10618

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.217 AC: 14741 AN: 68004

Other (OTH) AF: 0.187 AC: 394 AN: 2112

Alfa AF: 0.198 Hom.: 10852

Bravo AF: 0.153

TwinsUK AF: 0.221 AC: 821

ALSPAC AF: 0.217 AC: 837

ESP6500AA AF: 0.0545 AC: 240

ESP6500EA AF: 0.225 AC: 1937

ExAC AF: 0.162 AC: 19628

Asia WGS AF: 0.0710 AC: 250 AN: 3476

EpiCase AF: 0.228

EpiControl AF: 0.232

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Carnitine palmitoyltransferase II deficiency (4)
-	-	3	not specified (3)
-	-	2	Carnitine palmitoyl transferase II deficiency, severe infantile form (2)
-	-	2	not provided (2)
-	-	1	Carnitine palmitoyl transferase II deficiency, neonatal form (1)
-	-	1	Carnitine palmitoyl transferase II deficiency, severe infantile form;C1833518:Carnitine palmitoyl transferase II deficiency, neonatal form (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.075
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.89	L
PhyloP100		7.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.28
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.010	D
Polyphen		0.0020	B
Vest4		0.071
MPC		0.12
ClinPred		0.013	T
GERP RS		5.9
Varity_R		0.23
gMVP		0.59
Mutation Taster		=62/38	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1799822; hg19: chr1-53679229; COSMIC: COSV53759353; COSMIC: COSV53759353;