rs1799821

Variant names:

• chr1-53210776-G-A
• rs1799821
• NM_000098.3:c.1102G>A

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.1102G>A​(p.Val368Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,613,682 control chromosomes in the GnomAD database, including 222,450 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. V368V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.46 (17298 hom., cov: 32)
  • Exomes 𝑓: 0.52 (205152 hom.)
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.0480
• Publications: 84 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: ClinGen, Myriad Women’s Health
• carnitine palmitoyl transferase II deficiency, myopathic form

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia
• carnitine palmitoyl transferase II deficiency, neonatal form

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

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, 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=1.4549217E-6).
• BP6: Variant 1-53210776-G-A is Benign according to our data. Variant chr1-53210776-G-A is described in ClinVar as Benign. ClinVar VariationId is 92429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.703 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT2	NM_000098.3	MANE Select	c.1102G>A	p.Val368Ile	missense	Exon 4 of 5	NP_000089.1
	CPT2	NM_001330589.2		c.1102G>A	p.Val368Ile	missense	Exon 4 of 5	NP_001317518.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT2	ENST00000371486.4	TSL:1 MANE Select	c.1102G>A	p.Val368Ile	missense	Exon 4 of 5	ENSP00000360541.3
	CPT2	ENST00000637252.1	TSL:5	c.1102G>A	p.Val368Ile	missense	Exon 4 of 6	ENSP00000490492.1
	CPT2	ENST00000635862.1	TSL:5	c.1102G>A	p.Val368Ile	missense	Exon 4 of 6	ENSP00000490867.1

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69707 AN: 151872 Hom.: 17289 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.449

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.723

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.445

GnomAD2 exomes AF: 0.488 AC: 122480 AN: 251146 AF XY: 0.482

Gnomad AFR exome AF: 0.282

Gnomad AMR exome AF: 0.438

Gnomad ASJ exome AF: 0.499

Gnomad EAS exome AF: 0.728

Gnomad FIN exome AF: 0.535

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.484

GnomAD4 exome AF: 0.522 AC: 762983 AN: 1461692 Hom.: 205152 Cov.: 60 AF XY: 0.515 AC XY: 374539 AN XY: 727142

African (AFR) AF: 0.284 AC: 9510 AN: 33478

American (AMR) AF: 0.432 AC: 19327 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.498 AC: 13012 AN: 26132

East Asian (EAS) AF: 0.714 AC: 28344 AN: 39698

South Asian (SAS) AF: 0.269 AC: 23169 AN: 86252

European-Finnish (FIN) AF: 0.529 AC: 28264 AN: 53408

Middle Eastern (MID) AF: 0.368 AC: 2122 AN: 5766

European-Non Finnish (NFE) AF: 0.548 AC: 608949 AN: 1111854

Other (OTH) AF: 0.502 AC: 30286 AN: 60388

GnomAD4 genome AF: 0.459 AC: 69747 AN: 151990 Hom.: 17298 Cov.: 32 AF XY: 0.454 AC XY: 33736 AN XY: 74278

African (AFR) AF: 0.289 AC: 11988 AN: 41440

American (AMR) AF: 0.449 AC: 6868 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1730 AN: 3466

East Asian (EAS) AF: 0.722 AC: 3734 AN: 5170

South Asian (SAS) AF: 0.272 AC: 1307 AN: 4814

European-Finnish (FIN) AF: 0.530 AC: 5587 AN: 10542

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36854 AN: 67966

Other (OTH) AF: 0.451 AC: 952 AN: 2110

Alfa AF: 0.516 Hom.: 98395

Bravo AF: 0.452

TwinsUK AF: 0.542 AC: 2009

ALSPAC AF: 0.549 AC: 2116

ESP6500AA AF: 0.290 AC: 1278

ESP6500EA AF: 0.542 AC: 4658

ExAC AF: 0.483 AC: 58689

Asia WGS AF: 0.438 AC: 1523 AN: 3478

EpiCase AF: 0.530

EpiControl AF: 0.527

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Carnitine palmitoyltransferase II deficiency (4)
-	-	3	not provided (3)
-	-	1	Carnitine palmitoyl transferase II deficiency, neonatal form (1)
-	-	1	Carnitine palmitoyl transferase II deficiency, severe infantile form (1)
-	-	1	CPT2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.072
DANN	Benign	0.72
DEOGEN2	Benign	0.28	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.74	N
PhyloP100		-0.048
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.11	N
REVEL	Benign	0.23
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.011	B
Vest4		0.028
MPC		0.095
ClinPred		0.0050	T
GERP RS		-0.26
Varity_R		0.010
gMVP		0.11
Mutation Taster		=97/3	polymorphism (auto)

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: rs1799821; hg19: chr1-53676448; COSMIC: COSV53758728; COSMIC: COSV53758728;