rs749791796

Variant names:

• chr19-49701530-G-A
• rs749791796
• NM_001199753.2:c.589G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-49701530-G-A
• chr19-49701530-G-C
• chr19-49701530-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001199753.2(CPT1C):​c.589G>A​(p.Glu197Lys) 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 1,459,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CPT1C NM_001199753.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.92
• Publications: 1 publications found

Genes affected

CPT1C (HGNC:18540): (carnitine palmitoyltransferase 1C) This gene encodes a member of the carnitine/choline acetyltransferase family. The encoded protein regulates the beta-oxidation and transport of long-chain fatty acids into mitochondria, and may play a role in the regulation of feeding behavior and whole-body energy homeostasis. Alternatively spliced transcript variants encoding multiple protein isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

CPT1C Gene-Disease associations (from GenCC):

• hereditary spastic paraplegia 73

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• hereditary spastic paraplegia

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25665152).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT1C	NM_001199753.2	c.589G>A	p.Glu197Lys	missense_variant	Exon 7 of 20	ENST00000598293.6	NP_001186682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT1C	ENST00000598293.6	c.589G>A	p.Glu197Lys	missense_variant	Exon 7 of 20	2	NM_001199753.2	ENSP00000473028.1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459972 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726152

African (AFR) AF: 0.00 AC: 0 AN: 33372

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26088

East Asian (EAS) AF: 0.00 AC: 0 AN: 39606

South Asian (SAS) AF: 0.00 AC: 0 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110806

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 29

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 73 Uncertain:1

Apr 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The lysine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CPT1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 197 of the CPT1C protein (p.Glu197Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;D;T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.71	.;.;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Uncertain	-0.0064	T
MutationAssessor	Benign	1.6	L;L;.;L;L
PhyloP100		1.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.4	N;N;.;.;N
REVEL	Benign	0.26
Sift	Benign	0.23	T;T;.;.;T
Sift4G	Benign	0.24	T;T;T;T;T
Polyphen		0.0010	B;B;.;B;B
Vest4		0.28
MutPred		0.60		Loss of stability (P = 0.0119);Loss of stability (P = 0.0119);Loss of stability (P = 0.0119);Loss of stability (P = 0.0119);Loss of stability (P = 0.0119);
MVP		0.88
MPC		0.44
ClinPred		0.54	D
GERP RS		3.3
Varity_R		0.17
gMVP		0.43
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs749791796; hg19: chr19-50204787;