chr1-53196953-C-T

Variant names:

• chr1-53196953-C-T
• NM_000098.3:c.10C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000098.3(CPT2):​c.10C>T​(p.Arg4Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R4R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CPT2 NM_000098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.823
• 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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30234158).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT2	NM_000098.3	c.10C>T	p.Arg4Cys	missense_variant	Exon 1 of 5	ENST00000371486.4	NP_000089.1
CPT2	NM_001330589.2	c.10C>T	p.Arg4Cys	missense_variant	Exon 1 of 5		NP_001317518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT2	ENST00000371486.4	c.10C>T	p.Arg4Cys	missense_variant	Exon 1 of 5	1	NM_000098.3	ENSP00000360541.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1390228 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 688030

African (AFR) AF: 0.00 AC: 0 AN: 29644

American (AMR) AF: 0.00 AC: 0 AN: 38990

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24852

East Asian (EAS) AF: 0.00 AC: 0 AN: 34824

South Asian (SAS) AF: 0.00 AC: 0 AN: 79274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4194

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084974

Other (OTH) AF: 0.00 AC: 0 AN: 57736

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 01, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	0.0098	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.;.;T;T;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.19	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.30	T;T;T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.9	M;.;.;.;.;.
PhyloP100		0.82
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.88	N;.;.;.;.;.
REVEL	Uncertain	0.33
Sift	Uncertain	0.0060	D;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;.;.;.;.;.
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.11
MutPred		0.49		Gain of catalytic residue at L5 (P = 0.0084);Gain of catalytic residue at L5 (P = 0.0084);Gain of catalytic residue at L5 (P = 0.0084);Gain of catalytic residue at L5 (P = 0.0084);Gain of catalytic residue at L5 (P = 0.0084);Gain of catalytic residue at L5 (P = 0.0084);
MVP		0.92
MPC		0.16
ClinPred		0.69	D
GERP RS		1.3
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.20
gMVP		0.56
Mutation Taster		=95/5	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

hg19: chr1-53662625;