chr1-53213385-G-A

Variant names:

• chr1-53213385-G-A
• rs77565483
• NM_000098.3:c.1767G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000098.3(CPT2):​c.1767G>A​(p.Thr589Thr) 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 (★★).

• 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:13
• Conservation: PhyloP100: -2.78
• Publications: 1 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 -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR,Unknown gene

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.1767G>A	p.Thr589Thr	synonymous	Exon 5 of 5	NP_000089.1
	CPT2	NM_001330589.2		c.1698G>A	p.Thr566Thr	synonymous	Exon 5 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.1767G>A	p.Thr589Thr	synonymous	Exon 5 of 5	ENSP00000360541.3
	CPT2	ENST00000873097.1		c.1833G>A	p.Thr611Thr	synonymous	Exon 6 of 6	ENSP00000543156.1
	CPT2	ENST00000637252.1	TSL:5	c.1803G>A	p.Thr601Thr	synonymous	Exon 6 of 6	ENSP00000490492.1

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

GnomAD2 exomes AF: 0.00422 AC: 1062 AN: 251482 AF XY: 0.00366

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 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

African (AFR) AF: 0.0250 AC: 836 AN: 33480

American (AMR) AF: 0.00796 AC: 356 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00811 AC: 212 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000267 AC: 23 AN: 86258

European-Finnish (FIN) AF: 0.000580 AC: 31 AN: 53420

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5768

European-Non Finnish (NFE) AF: 0.00173 AC: 1919 AN: 1112012

Other (OTH) AF: 0.00634 AC: 383 AN: 60396

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

African (AFR) AF: 0.0248 AC: 1031 AN: 41564

American (AMR) AF: 0.0150 AC: 229 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.000941 AC: 10 AN: 10624

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00203 AC: 138 AN: 68034

Other (OTH) AF: 0.0128 AC: 27 AN: 2110

Alfa AF: 0.00874 Hom.: 15

Bravo AF: 0.0124

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.00284

EpiControl AF: 0.00308

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.30
DANN	Benign	0.68
PhyloP100		-2.8
Mutation Taster		=98/2	polymorphism

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: rs77565483; hg19: chr1-53679057;