Genetic Variant ECI2:p.Lys295Met (chr6-4119187-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_206836.3(ECI2):c.884A>T(p.Lys295Met) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K295T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

ECI2
NM_206836.3 missense, splice_region

Scores

Splicing: ADA: 0.9999

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.92

Publications

0 publications found

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]

ECI2 links:

TEX56P (HGNC:):

TEX56P links:

TEX56P (HGNC:21620): (testis expressed 56, pseudogene)

TEX56P links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206836.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ECI2	NM_206836.3	MANE Select	c.884A>T	p.Lys295Met	missense splice_region	Exon 8 of 10	NP_996667.2	O75521-1
ECI2	NM_001166010.2		c.794A>T	p.Lys265Met	missense splice_region	Exon 8 of 10	NP_001159482.1	A0A0C4DGA2
ECI2	NM_006117.3		c.794A>T	p.Lys265Met	missense splice_region	Exon 8 of 10	NP_006108.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ECI2	ENST00000380118.8	TSL:1 MANE Select	c.884A>T	p.Lys295Met	missense splice_region	Exon 8 of 10	ENSP00000369461.3	O75521-1
ECI2	ENST00000361538.6	TSL:1	c.794A>T	p.Lys265Met	missense splice_region	Exon 8 of 10	ENSP00000354737.2	A0A0C4DGA2
ECI2	ENST00000380125.6	TSL:1	c.794A>T	p.Lys265Met	missense splice_region	Exon 8 of 10	ENSP00000369468.2	A0A0C4DGA2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.048

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.044

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.4

PhyloP100

6.9

PrimateAI

Uncertain

0.56

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.56

Sift

Benign

0.038

Sift4G

Benign

0.065

Polyphen

1.0

Vest4

0.87

MutPred

0.59

Loss of ubiquitination at K295 (P = 0.0326)

MVP

0.64

MPC

0.43

ClinPred

1.0

GERP RS

5.9

Varity_R

0.83

gMVP

0.92

Mutation Taster

=14/86

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

1.0

SpliceAI score (max)

0.61

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.61

Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over