NM_001199753.2:c.2092A>G

Variant names:

• chr19-49712808-A-G
• rs143091111
• NM_001199753.2:c.2092A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001199753.2(CPT1C):​c.2092A>G​(p.Asn698Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000734 in 1,613,976 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N698S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00076 (3 hom.)
• Consequence: CPT1C NM_001199753.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1 O:1
• Conservation: PhyloP100: 5.83
• Publications: 4 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03134325).
• BP6: Variant 19-49712808-A-G is Benign according to our data. Variant chr19-49712808-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 476175.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000493 (75/152100) while in subpopulation AMR AF = 0.000917 (14/15274). AF 95% confidence interval is 0.000612. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 75 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001199753.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1C	NM_001199753.2	MANE Select	c.2092A>G	p.Asn698Asp	missense	Exon 18 of 20	NP_001186682.1
	CPT1C	NM_001378482.1		c.2158A>G	p.Asn720Asp	missense	Exon 17 of 19	NP_001365411.1
	CPT1C	NM_001199752.3		c.2092A>G	p.Asn698Asp	missense	Exon 18 of 20	NP_001186681.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPT1C	ENST00000598293.6	TSL:2 MANE Select	c.2092A>G	p.Asn698Asp	missense	Exon 18 of 20	ENSP00000473028.1
	CPT1C	ENST00000323446.9	TSL:1	c.2092A>G	p.Asn698Asp	missense	Exon 17 of 19	ENSP00000319343.4
	CPT1C	ENST00000405931.6	TSL:1	c.2059A>G	p.Asn687Asp	missense	Exon 18 of 20	ENSP00000384465.2

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 151982 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000918

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000779

Gnomad OTH AF: 0.000961

GnomAD2 exomes AF: 0.000517 AC: 130 AN: 251476 AF XY: 0.000508

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000686

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.000759 AC: 1109 AN: 1461876 Hom.: 3 Cov.: 31 AF XY: 0.000718 AC XY: 522 AN XY: 727242

African (AFR) AF: 0.0000597 AC: 2 AN: 33478

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000220 AC: 19 AN: 86258

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.000888 AC: 988 AN: 1111996

Other (OTH) AF: 0.000778 AC: 47 AN: 60396

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152100 Hom.: 0 Cov.: 30 AF XY: 0.000417 AC XY: 31 AN XY: 74356

African (AFR) AF: 0.000121 AC: 5 AN: 41480

American (AMR) AF: 0.000917 AC: 14 AN: 15274

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.000779 AC: 53 AN: 68000

Other (OTH) AF: 0.000951 AC: 2 AN: 2104

Alfa AF: 0.000641 Hom.: 0

Bravo AF: 0.000635

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000585 AC: 71

EpiCase AF: 0.000981

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia 73 Uncertain:1 Benign:1 Other:1

Apr 25, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GenomeConnect - Invitae Patient Insights Network

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Uncertain significance and reported on 04-30-2021 by Invitae. GenomeConnect-InvitaePIN assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

not provided Uncertain:1

Sep 17, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Benign	0.092
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.031	T
MetaSVM	Uncertain	-0.025	T
MutationAssessor	Benign	1.9	L
PhyloP100		5.8
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.39
Sift	Benign	0.12	T
Sift4G	Benign	0.11	T
Polyphen		0.041	B
Vest4		0.35
MVP		0.86
MPC		0.88
ClinPred		0.046	T
GERP RS		3.6
PromoterAI		0.056	Neutral
Varity_R		0.18
gMVP		0.45
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

dbSNP: rs143091111; hg19: chr19-50216065;