2-118843024-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001426.4(EN1):ā€‹c.1093A>Gā€‹(p.Lys365Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000128 in 1,614,030 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000046 ( 0 hom., cov: 32)
Exomes š‘“: 0.00014 ( 0 hom. )

Consequence

EN1
NM_001426.4 missense

Scores

6
12
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.12
Variant links:
Genes affected
EN1 (HGNC:3342): (engrailed homeobox 1) Homeobox-containing genes are thought to have a role in controlling development. In Drosophila, the 'engrailed' (en) gene plays an important role during development in segmentation, where it is required for the formation of posterior compartments. Different mutations in the mouse homologs, En1 and En2, produced different developmental defects that frequently are lethal. The human engrailed homologs 1 and 2 encode homeodomain-containing proteins and have been implicated in the control of pattern formation during development of the central nervous system. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EN1NM_001426.4 linkuse as main transcriptc.1093A>G p.Lys365Glu missense_variant 2/2 ENST00000295206.7 NP_001417.3 Q05925

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EN1ENST00000295206.7 linkuse as main transcriptc.1093A>G p.Lys365Glu missense_variant 2/22 NM_001426.4 ENSP00000295206.5 Q05925

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152166
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000882
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000717
AC:
18
AN:
251154
Hom.:
0
AF XY:
0.0000662
AC XY:
9
AN XY:
135858
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000137
AC:
200
AN:
1461864
Hom.:
0
Cov.:
32
AF XY:
0.000128
AC XY:
93
AN XY:
727240
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:
0.000174
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152166
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000882
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.000148
AC:
18
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

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 GeneticsDec 06, 2023The c.1093A>G (p.K365E) alteration is located in exon 2 (coding exon 2) of the EN1 gene. This alteration results from a A to G substitution at nucleotide position 1093, causing the lysine (K) at amino acid position 365 to be replaced by a glutamic acid (E). 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
1.0
BayesDel_addAF
Uncertain
0.017
T
BayesDel_noAF
Uncertain
0.050
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.36
D
MetaRNN
Uncertain
0.64
D
MetaSVM
Pathogenic
0.79
D
MutationAssessor
Uncertain
2.5
M
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-3.5
D
REVEL
Pathogenic
0.69
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0030
D
Polyphen
0.72
P
Vest4
0.61
MVP
0.87
ClinPred
0.79
D
GERP RS
5.1
Varity_R
0.91
gMVP
0.86

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: rs765343713; hg19: chr2-119600600; API