NM_001876.4:c.2260C>G

Variant names:

• chr11-68757706-G-C
• rs144781827
• NM_001876.4:c.2260C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001876.4(CPT1A):​c.2260C>G​(p.Leu754Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L754L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CPT1A NM_001876.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.03

Genes affected

CPT1A (HGNC:2328): (carnitine palmitoyltransferase 1A) The mitochondrial oxidation of long-chain fatty acids is initiated by the sequential action of carnitine palmitoyltransferase I (which is located in the outer membrane and is detergent-labile) and carnitine palmitoyltransferase II (which is located in the inner membrane and is detergent-stable), together with a carnitine-acylcarnitine translocase. CPT I is the key enzyme in the carnitine-dependent transport across the mitochondrial inner membrane and its deficiency results in a decreased rate of fatty acid beta-oxidation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32558668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT1A	NM_001876.4	c.2260C>G	p.Leu754Val	missense_variant	Exon 19 of 19	ENST00000265641.10	NP_001867.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT1A	ENST00000265641.10	c.2260C>G	p.Leu754Val	missense_variant	Exon 19 of 19	1	NM_001876.4	ENSP00000265641.4
CPT1A	ENST00000376618.6	c.2235+1863C>G		intron_variant	Intron 18 of 18	1		ENSP00000365803.2
CPT1A	ENST00000540367.5	c.2235+1863C>G		intron_variant	Intron 17 of 17	1		ENSP00000439084.1
CPT1A	ENST00000539743.5	c.2260C>G	p.Leu754Val	missense_variant	Exon 18 of 18	5		ENSP00000446108.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249312 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134950

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461808 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727198

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Uncertain	0.54	D;D
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.86
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	.;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	0.79	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.28	N;N
REVEL	Benign	0.26
Sift	Benign	0.049	D;D
Sift4G	Uncertain	0.051	T;T
Polyphen		0.0010	B;B
Vest4		0.32
MutPred		0.67		Gain of methylation at K755 (P = 0.0415);Gain of methylation at K755 (P = 0.0415);
MVP		0.65
MPC		0.47
ClinPred		0.050	T
GERP RS		-0.56
Varity_R		0.065
gMVP		0.53

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: rs144781827; hg19: chr11-68525174;