rs143478074

Positions:

• chr19-49711857-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001199753.2(CPT1C):​c.1915G>A​(p.Ala639Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,613,954 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (9 hom.)
• Consequence: CPT1C NM_001199753.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.145

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077616274).
• BP6: Variant 19-49711857-G-A is Benign according to our data. Variant chr19-49711857-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 476174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00215 (328/152346) while in subpopulation NFE AF= 0.00351 (239/68036). AF 95% confidence interval is 0.00315. There are 1 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 328 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPT1C	NM_001199753.2	c.1915G>A	p.Ala639Thr	missense_variant	17/20	ENST00000598293.6	NP_001186682.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPT1C	ENST00000598293.6	c.1915G>A	p.Ala639Thr	missense_variant	17/20	2	NM_001199753.2	ENSP00000473028.1

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 328 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00351

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00238 AC: 598 AN: 251060 Hom.: 1 AF XY: 0.00228 AC XY: 310 AN XY: 135766

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00461

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00334 AC: 4882 AN: 1461608 Hom.: 9 Cov.: 30 AF XY: 0.00324 AC XY: 2358 AN XY: 727130

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00122

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.00412

Gnomad4 NFE exome AF: 0.00391

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00215 AC: 328 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74512

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00348

Gnomad4 NFE AF: 0.00351

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00303 Hom.: 2

Bravo AF: 0.00229

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00233 AC: 20

ExAC AF: 0.00263 AC: 319

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2022	CPT1C: BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CPT1C-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary spastic paraplegia 73 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.22	T;T;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.50	.;.;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0078	T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L;L;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.11	N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.57	T;T;.;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0010	B;B;B;B
Vest4		0.25
MVP		0.68
MPC		0.85
ClinPred		0.018	T
GERP RS		2.3
Varity_R		0.026
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143478074; hg19: chr19-50215114;