chr7-87361557-G-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_021151.4(CROT):c.408G>C(p.Trp136Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,593,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
CROT
NM_021151.4 missense
NM_021151.4 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 9.62
Genes affected
CROT (HGNC:2366): (carnitine O-octanoyltransferase) This gene encodes a member of the carnitine/choline acetyltransferase family. The encoded protein converts 4,8-dimethylnonanoyl-CoA to its corresponding carnitine ester. This transesterification occurs in the peroxisome and is necessary for transport of medium- and long- chain acyl-CoA molecules out of the peroxisome to the cytosol and mitochondria. The protein thus plays a role in lipid metabolism and fatty acid beta-oxidation. Alternatively spliced transcript variants have been described.[provided by RefSeq, Jan 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.956
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CROT | NM_021151.4 | c.408G>C | p.Trp136Cys | missense_variant | 5/18 | ENST00000331536.8 | |
CROT | NM_001143935.2 | c.492G>C | p.Trp164Cys | missense_variant | 6/19 | ||
CROT | XM_011516337.4 | c.408G>C | p.Trp136Cys | missense_variant | 5/18 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CROT | ENST00000331536.8 | c.408G>C | p.Trp136Cys | missense_variant | 5/18 | 1 | NM_021151.4 | P1 | |
CROT | ENST00000419147.6 | c.492G>C | p.Trp164Cys | missense_variant | 6/19 | 2 | |||
CROT | ENST00000442291.1 | c.408G>C | p.Trp136Cys | missense_variant | 4/17 | 5 | |||
CROT | ENST00000488850.1 | n.115G>C | non_coding_transcript_exon_variant | 1/3 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000118 AC: 28AN: 236610Hom.: 0 AF XY: 0.000109 AC XY: 14AN XY: 128060
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GnomAD4 exome AF: 0.000142 AC: 204AN: 1440988Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 83AN XY: 714856
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GnomAD4 genome ? AF: 0.0000920 AC: 14AN: 152158Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2022 | The c.492G>C (p.W164C) alteration is located in exon 6 (coding exon 4) of the CROT gene. This alteration results from a G to C substitution at nucleotide position 492, causing the tryptophan (W) at amino acid position 164 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Polyphen
1.0
.;D;.
Vest4
MutPred
0.66
.;Loss of MoRF binding (P = 0.0107);Loss of MoRF binding (P = 0.0107);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at