1-53211252-T-C

Variant names:

• chr1-53211252-T-C
• rs113493395
• NM_000098.3:c.1578T>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PVS1_Strong BP6_Very_Strong BS2

The NM_001330589.2(CPT2):​c.1576+2T>C variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,612,504 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0039 (36 hom.)
• Consequence: CPT2 NM_001330589.2 splice_donor, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -2.08
• Publications: 0 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 -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.6477987 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 1-53211252-T-C is Benign according to our data. Variant chr1-53211252-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 297609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330589.2. 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.1578T>C	p.Gly526Gly	synonymous	Exon 4 of 5	NP_000089.1
	CPT2	NM_001330589.2		c.1576+2T>C		splice_donor intron	N/A	NP_001317518.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT2	ENST00000371486.4	TSL:1 MANE Select	c.1578T>C	p.Gly526Gly	synonymous	Exon 4 of 5	ENSP00000360541.3
	CPT2	ENST00000873097.1		c.1578T>C	p.Gly526Gly	synonymous	Exon 4 of 6	ENSP00000543156.1
	CPT2	ENST00000637252.1	TSL:5	c.1578T>C	p.Gly526Gly	synonymous	Exon 4 of 6	ENSP00000490492.1

Frequencies

GnomAD3 genomes AF: 0.00432 AC: 658 AN: 152140 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0275

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00422 AC: 1044 AN: 247360 AF XY: 0.00411

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.000525

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0248

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00314

GnomAD4 exome AF: 0.00394 AC: 5756 AN: 1460246 Hom.: 36 Cov.: 34 AF XY: 0.00379 AC XY: 2749 AN XY: 726244

African (AFR) AF: 0.000688 AC: 23 AN: 33442

American (AMR) AF: 0.000561 AC: 25 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.000280 AC: 24 AN: 85852

European-Finnish (FIN) AF: 0.0250 AC: 1331 AN: 53320

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00367 AC: 4080 AN: 1111262

Other (OTH) AF: 0.00444 AC: 268 AN: 60326

GnomAD4 genome AF: 0.00432 AC: 658 AN: 152258 Hom.: 4 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74446

African (AFR) AF: 0.000698 AC: 29 AN: 41556

American (AMR) AF: 0.00274 AC: 42 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.0275 AC: 292 AN: 10608

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

European-Non Finnish (NFE) AF: 0.00422 AC: 287 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2106

Alfa AF: 0.00301 Hom.: 1

Bravo AF: 0.00223

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00489 AC: 42

ExAC AF: 0.00392 AC: 476

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	Carnitine palmitoyltransferase II deficiency (3)
-	-	2	not specified (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	-0.89
CADD	Benign	0.72
DANN	Benign	0.49
FATHMM_MKL	Benign	0.048	N
PhyloP100		-2.1
GERP RS		-5.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs113493395; hg19: chr1-53676924;