chr1-53197050-A-AGC

Variant names:

• chr1-53197050-A-AGC
• rs754363068
• NM_000098.3:c.110_111dupGC

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000098.3(CPT2):​c.110_111dupGC​(p.Ser38AlafsTer36) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,538,902 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001361325: The most pronounced variant effect results in 10%-<30% of normal muscle CPT residual enzyme activity in a compound heterozygous genotype (Martin_2000).". Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: CPT2 NM_000098.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 0.0970
• Publications: 3 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)

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001361325: The most pronounced variant effect results in 10%-<30% of normal muscle CPT residual enzyme activity in a compound heterozygous genotype (Martin_2000).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-53197050-A-AGC is Pathogenic according to our data. Variant chr1-53197050-A-AGC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 371697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.110_111dupGC	p.Ser38AlafsTer36	frameshift	Exon 1 of 5	NP_000089.1	P23786
	CPT2	NM_001330589.2		c.110_111dupGC	p.Ser38AlafsTer36	frameshift	Exon 1 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.110_111dupGC	p.Ser38AlafsTer36	frameshift	Exon 1 of 5	ENSP00000360541.3	P23786
	CPT2	ENST00000873097.1		c.110_111dupGC	p.Ser38AlafsTer36	frameshift	Exon 1 of 6	ENSP00000543156.1
	CPT2	ENST00000637252.1	TSL:5	c.110_111dupGC	p.Ser38AlafsTer36	frameshift	Exon 1 of 6	ENSP00000490492.1	A0A1B0GVF3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000377 AC: 5 AN: 132500 AF XY: 0.0000277

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000164

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000205

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000151 AC: 21 AN: 1386844 Hom.: 0 Cov.: 30 AF XY: 0.0000146 AC XY: 10 AN XY: 684562

African (AFR) AF: 0.00 AC: 0 AN: 31538

American (AMR) AF: 0.000196 AC: 7 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25116

East Asian (EAS) AF: 0.00 AC: 0 AN: 35724

South Asian (SAS) AF: 0.00 AC: 0 AN: 79210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1078402

Other (OTH) AF: 0.0000346 AC: 2 AN: 57872

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74272

African (AFR) AF: 0.0000242 AC: 1 AN: 41402

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67976

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.097
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754363068; hg19: chr1-53662722;