19-49692391-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_001199753.2(CPT1C):c.139T>C(p.Trp47Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CPT1C NM_001199753.2 missense, splice_region
• Scores: Splicing: ADA: 0.001778
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.522

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0789465).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000118 (18/152326) while in subpopulation AMR AF= 0.000719 (11/15290). AF 95% confidence interval is 0.000403. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT1C	NM_001199753.2	c.139T>C	p.Trp47Arg	missense_variant, splice_region_variant	3/20	ENST00000598293.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1C	ENST00000598293.6	c.139T>C	p.Trp47Arg	missense_variant, splice_region_variant	3/20	2	NM_001199753.2	P1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152208 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.000478

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251086 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135702

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000203

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: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727226

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000224

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: 0.00000540

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152326 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74478

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000719

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000119 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.139T>C (p.W47R) alteration is located in exon 3 (coding exon 1) of the CPT1C gene. This alteration results from a T to C substitution at nucleotide position 139, causing the tryptophan (W) at amino acid position 47 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	17
Dann	Benign	0.87
DEOGEN2	Benign	0.15	T;T;T;T;.;.;T;.
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.69	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.60	N;N;.;N;N;.;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	1.9	N;N;.;.;N;.;.;.
REVEL	Benign	0.29
Sift	Benign	0.67	T;T;.;.;T;.;.;.
Sift4G	Benign	0.81	T;T;T;T;T;T;T;T
Polyphen		0.0	B;B;.;B;B;.;.;.
Vest4		0.36
MutPred		0.47		Gain of methylation at W47 (P = 0.0103);Gain of methylation at W47 (P = 0.0103);Gain of methylation at W47 (P = 0.0103);Gain of methylation at W47 (P = 0.0103);Gain of methylation at W47 (P = 0.0103);Gain of methylation at W47 (P = 0.0103);Gain of methylation at W47 (P = 0.0103);Gain of methylation at W47 (P = 0.0103);
MVP		0.80
MPC		0.69
ClinPred		0.020	T
GERP RS		3.5
Varity_R		0.13
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0018
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.010		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: rs140961441; hg19: chr19-50195648;