19-49697384-G-A

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.200G>A(p.Ser67Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000358 in 1,613,996 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00038 (1 hom.)
• Consequence: CPT1C NM_001199753.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.839

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=0.106076986).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152116) while in subpopulation NFE AF= 0.000309 (21/68014). AF 95% confidence interval is 0.000207. There are 0 homozygotes in gnomad4. There are 7 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 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPT1C	NM_001199753.2	c.200G>A	p.Ser67Asn	missense_variant	4/20	ENST00000598293.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPT1C	ENST00000598293.6	c.200G>A	p.Ser67Asn	missense_variant	4/20	2	NM_001199753.2	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152116 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000127 AC: 32 AN: 251476 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135904

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: 0.000273

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000380 AC: 555 AN: 1461880 Hom.: 1 Cov.: 31 AF XY: 0.000364 AC XY: 265 AN XY: 727238

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000466

Gnomad4 OTH exome AF: 0.000563

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152116 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74302

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000280 Hom.: 0

Bravo AF: 0.000178

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 06, 2021

The c.200G>A (p.S67N) alteration is located in exon 4 (coding exon 2) of the CPT1C gene. This alteration results from a G to A substitution at nucleotide position 200, causing the serine (S) at amino acid position 67 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hereditary spastic paraplegia 73 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 14, 2023

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 67 of the CPT1C protein (p.Ser67Asn). This variant is present in population databases (rs151219989, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CPT1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 1035925). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	0.98
DEOGEN2	Benign	0.11	T;T;T;T;.;.;T;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.078	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	1.2	L;L;.;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.2	N;N;.;.;N;.;.;.
REVEL	Benign	0.28
Sift	Benign	0.18	T;T;.;.;T;.;.;.
Sift4G	Benign	0.25	T;T;T;T;T;D;T;D
Polyphen		0.56	P;P;.;P;P;.;.;.
Vest4		0.41
MVP		0.76
MPC		0.52
ClinPred		0.049	T
GERP RS		1.3
Varity_R		0.076
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs151219989; hg19: chr19-50200641;