NM_152246.3:c.2084G>A

Variant names:

• chr22-50570351-C-T
• rs933303732
• NM_152246.3:c.2084G>A

Variant summary

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

The NM_152246.3(CPT1B):​c.2084G>A​(p.Arg695His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,455,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R695G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CPT1B NM_152246.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.799
• Publications: 0 publications found

Genes affected

CPT1B (HGNC:2329): (carnitine palmitoyltransferase 1B) The protein encoded by this gene, a member of the carnitine/choline acetyltransferase family, is the rate-controlling enzyme of the long-chain fatty acid beta-oxidation pathway in muscle mitochondria. This enzyme is required for the net transport of long-chain fatty acyl-CoAs from the cytoplasm into the mitochondria. Multiple transcript variants encoding different isoforms have been found for this gene, and read-through transcripts are expressed from the upstream locus that include exons from this gene. [provided by RefSeq, Jun 2009]

CHKB-CPT1B (HGNC:41998): (CHKB-CPT1B readthrough (NMD candidate)) The genes CHKB and CPT1B are adjacent on chromosome 22 and read-through transcripts are expressed that include exons from both loci. The read-through transcripts are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to express proteins. [provided by RefSeq, Jun 2009]

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=0.10006556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPT1B	NM_152246.3	c.2084G>A	p.Arg695His	missense_variant	Exon 17 of 20	ENST00000312108.12	NP_689452.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPT1B	ENST00000312108.12	c.2084G>A	p.Arg695His	missense_variant	Exon 17 of 20	1	NM_152246.3	ENSP00000312189.8
CHKB-CPT1B	ENST00000453634.5	n.*2309G>A		non_coding_transcript_exon_variant	Exon 20 of 23	5		ENSP00000457031.1
CHKB-CPT1B	ENST00000453634.5	n.*2309G>A		3_prime_UTR_variant	Exon 20 of 23	5		ENSP00000457031.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1455542 Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11 AN XY: 723774

African (AFR) AF: 0.0000300 AC: 1 AN: 33374

American (AMR) AF: 0.00 AC: 0 AN: 44268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25838

East Asian (EAS) AF: 0.00 AC: 0 AN: 39622

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53002

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5722

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1108096

Other (OTH) AF: 0.00 AC: 0 AN: 60098

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2084G>A (p.R695H) alteration is located in exon 17 (coding exon 16) of the CPT1B gene. This alteration results from a G to A substitution at nucleotide position 2084, causing the arginine (R) at amino acid position 695 to be replaced by a histidine (H). 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	0.071
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.42	T;T;T;T;.
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.51	.;.;.;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.42	N;N;N;N;.
PhyloP100		0.80
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.010	N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.
Vest4		0.14
MutPred		0.47		Loss of stability (P = 0.0973);Loss of stability (P = 0.0973);Loss of stability (P = 0.0973);Loss of stability (P = 0.0973);.;
MVP		0.79
ClinPred		0.13	T
GERP RS		2.2
Varity_R		0.035
gMVP		0.27
Mutation Taster		=90/10	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: rs933303732; hg19: chr22-51008780;