rs77565483

chr1-53213385-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000098.3(CPT2):c.1767G>A(p.Thr589=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,614,210 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. TSTLS589T?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0097 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (31 hom.)
• Consequence: CPT2 NM_000098.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -2.78

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 1-53213385-G-A is Benign according to our data. Variant chr1-53213385-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 92432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.78 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00972 (1480/152322) while in subpopulation AFR AF= 0.0248 (1031/41564). AF 95% confidence interval is 0.0235. There are 14 homozygotes in gnomad4. There are 699 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT2	NM_000098.3	c.1767G>A	p.Thr589=	synonymous_variant	5/5	ENST00000371486.4
CPT2	NM_001330589.2	c.1698G>A	p.Thr566=	synonymous_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT2	ENST00000371486.4	c.1767G>A	p.Thr589=	synonymous_variant	5/5	1	NM_000098.3	P1
	ENST00000629810.1	n.88C>T		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.00971 AC: 1478 AN: 152204 Hom.: 14 Cov.: 33

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0150

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00203

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00422 AC: 1062 AN: 251482 Hom.: 6 AF XY: 0.00366 AC XY: 498 AN XY: 135914

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00653

Gnomad ASJ exome AF: 0.00883

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00225

Gnomad OTH exome AF: 0.00929

GnomAD4 exome AF: 0.00262 AC: 3834 AN: 1461888 Hom.: 31 Cov.: 31 AF XY: 0.00247 AC XY: 1796 AN XY: 727246

Gnomad4 AFR exome AF: 0.0250

Gnomad4 AMR exome AF: 0.00796

Gnomad4 ASJ exome AF: 0.00811

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000580

Gnomad4 NFE exome AF: 0.00173

Gnomad4 OTH exome AF: 0.00634

GnomAD4 genome AF: 0.00972 AC: 1480 AN: 152322 Hom.: 14 Cov.: 33 AF XY: 0.00939 AC XY: 699 AN XY: 74480

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.0150

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00203

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00681 Hom.: 7

Bravo AF: 0.0124

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 06, 2019	Variant summary: CPT2 c.1767G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0042 in 251482 control chromosomes in the gnomAD database, including 6 homozygotes. The observed variant frequency is approximately 3-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in CPT2 causing Carnitine Palmitoyltransferase II Deficiency phenotype (0.0016), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1767G>A in individuals affected with Carnitine Palmitoyltransferase II Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

Carnitine palmitoyltransferase II deficiency Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Carnitine palmitoyl transferase II deficiency, neonatal form Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 24, 2021

- -

Carnitine palmitoyl transferase II deficiency, myopathic form Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Encephalopathy, acute, infection-induced, susceptibility to, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Carnitine palmitoyl transferase II deficiency, severe infantile form Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.30
Dann	Benign	0.68

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: rs77565483; hg19: chr1-53679057;