6-4119187-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_206836.3(ECI2):ā€‹c.884A>Cā€‹(p.Lys295Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000248 in 1,610,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 33)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

ECI2
NM_206836.3 missense, splice_region

Scores

7
9
3
Splicing: ADA: 0.9997
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.92
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]
TEX56P (HGNC:21620): (testis expressed 56, pseudogene)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.856

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ECI2NM_206836.3 linkuse as main transcriptc.884A>C p.Lys295Thr missense_variant, splice_region_variant 8/10 ENST00000380118.8 NP_996667.2
TEX56PNR_104463.3 linkuse as main transcriptn.1307-2762T>G intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ECI2ENST00000380118.8 linkuse as main transcriptc.884A>C p.Lys295Thr missense_variant, splice_region_variant 8/101 NM_206836.3 ENSP00000369461 P1O75521-1
TEX56PENST00000642280.1 linkuse as main transcriptn.616-2762T>G intron_variant, non_coding_transcript_variant
TEX56PENST00000643110.1 linkuse as main transcriptn.1050-2762T>G intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1458634
Hom.:
0
Cov.:
31
AF XY:
0.00000276
AC XY:
2
AN XY:
725646
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152214
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

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 GeneticsMar 24, 2023The c.884A>C (p.K295T) alteration is located in exon 8 (coding exon 8) of the ECI2 gene. This alteration results from a A to C substitution at nucleotide position 884, causing the lysine (K) at amino acid position 295 to be replaced by a threonine (T). 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
Uncertain
0.40
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Uncertain
0.13
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Benign
0.048
T;.;.;.
Eigen
Pathogenic
0.96
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;.;.;D
M_CAP
Benign
0.044
D
MetaRNN
Pathogenic
0.86
D;D;D;D
MetaSVM
Uncertain
-0.037
T
MutationAssessor
Pathogenic
4.2
H;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D
PrimateAI
Uncertain
0.61
T
PROVEAN
Pathogenic
-4.6
D;D;D;D
REVEL
Uncertain
0.55
Sift
Uncertain
0.0050
D;D;D;D
Sift4G
Uncertain
0.010
D;D;D;D
Polyphen
1.0
D;.;.;.
Vest4
0.90
MutPred
0.59
Loss of ubiquitination at K295 (P = 0.0326);.;.;.;
MVP
0.66
MPC
0.42
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.91
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.98
SpliceAI score (max)
0.47
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.47
Position offset: -1

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: rs1772494921; hg19: chr6-4119421; API