chr6-4119187-T-A

Variant names:

• chr6-4119187-T-A
• rs1772494921
• NM_206836.3:c.884A>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_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

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:):

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

ACMG classification

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

Sel.	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

Sel.	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.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.044	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		6.9
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.56
Sift	Benign	0.038	D
Sift4G	Benign	0.065	T
Polyphen		1.0	D
Vest4		0.87
MutPred		0.59		Loss of ubiquitination at K295 (P = 0.0326)
MVP		0.64
MPC		0.43
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.83
gMVP		0.92
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs1772494921; hg19: chr6-4119421;