6-4133559-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_206836.3(ECI2):ā€‹c.203T>Cā€‹(p.Leu68Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,948 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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ECI2
NM_206836.3 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.82
Variant links:
Genes affected
ECI2 (HGNC:14601): (enoyl-CoA delta isomerase 2) This gene encodes a member of the hydratase/isomerase superfamily. The protein encoded is a key mitochondrial enzyme involved in beta-oxidation of unsaturated fatty acids. It catalyzes the transformation of 3-cis and 3-trans-enoyl-CoA esters arising during the stepwise degradation of cis-, mono-, and polyunsaturated fatty acids to the 2-trans-enoyl-CoA intermediates. Alternatively spliced transcript variants have been described. [provided by RefSeq, Aug 2011]

Genome browser will be placed here

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, 0.981

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ECI2NM_206836.3 linkuse as main transcriptc.203T>C p.Leu68Pro missense_variant 2/10 ENST00000380118.8 NP_996667.2
ECI2NM_001166010.2 linkuse as main transcriptc.113T>C p.Leu38Pro missense_variant 2/10 NP_001159482.1
ECI2NM_006117.3 linkuse as main transcriptc.113T>C p.Leu38Pro missense_variant 2/10 NP_006108.2
ECI2NR_028588.2 linkuse as main transcriptn.208T>C non_coding_transcript_exon_variant 2/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ECI2ENST00000380118.8 linkuse as main transcriptc.203T>C p.Leu68Pro missense_variant 2/101 NM_206836.3 ENSP00000369461 P1O75521-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1458948
Hom.:
0
Cov.:
30
AF XY:
0.00000276
AC XY:
2
AN XY:
725664
show subpopulations
Gnomad4 AFR exome
AF:
0.0000600
Gnomad4 AMR exome
AF:
0.00
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.000108
Hom.:
1
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

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 submitterclinical testingAmbry GeneticsApr 06, 2022The c.203T>C (p.L68P) alteration is located in exon 2 (coding exon 2) of the ECI2 gene. This alteration results from a T to C substitution at nucleotide position 203, causing the leucine (L) at amino acid position 68 to be replaced by a proline (P). 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
Pathogenic
0.95
BayesDel_addAF
Pathogenic
0.32
D
BayesDel_noAF
Pathogenic
0.22
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.20
T;.;.;.;T
Eigen
Pathogenic
0.87
Eigen_PC
Pathogenic
0.71
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.96
D;.;.;D;D
M_CAP
Benign
0.046
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D
MetaSVM
Uncertain
-0.024
T
MutationAssessor
Pathogenic
4.8
H;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-6.0
D;D;D;D;D
REVEL
Uncertain
0.59
Sift
Pathogenic
0.0
D;D;D;D;D
Sift4G
Benign
0.074
T;T;T;T;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.93
MutPred
0.89
Loss of stability (P = 0.0018);.;.;.;.;
MVP
0.53
MPC
0.48
ClinPred
1.0
D
GERP RS
6.1
Varity_R
0.94
gMVP
0.92

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs576123622; hg19: chr6-4133793; API