Genetic Variant NM_001427.4:c.133C>T (chr7-155458510-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001427.4(EN2):c.133C>T(p.Arg45Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000255 in 1,177,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000025 ( 0 hom. )

Consequence

EN2
NM_001427.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

Publications

0 publications found

Variant links:

Genes affected

EN2 (HGNC:3343): (engrailed homeobox 2) 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]

EN2 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EN2	NM_001427.4 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 1 of 2	ENST00000297375.4	NP_001418.2	P19622

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EN2	ENST00000297375.4 link	c.133C>T	p.Arg45Trp	missense_variant	Exon 1 of 2	1	NM_001427.4	ENSP00000297375.4		P19622

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000255

AC:

AN:

1177350

Hom.:

Cov.:

AF XY:

0.00000176

AC XY:

AN XY:

569056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23476

American (AMR)

AF:

0.00

AC:

AN:

9742

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16274

East Asian (EAS)

AF:

0.0000369

AC:

AN:

27090

South Asian (SAS)

AF:

0.00

AC:

AN:

38294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4404

European-Non Finnish (NFE)

AF:

0.00000103

AC:

AN:

970664

Other (OTH)

AF:

0.0000211

AC:

AN:

47480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 27, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.133C>T (p.R45W) alteration is located in exon 1 (coding exon 1) of the EN2 gene. This alteration results from a C to T substitution at nucleotide position 133, causing the arginine (R) at amino acid position 45 to be replaced by a tryptophan (W). 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

Benign

0.34

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.90

MetaRNN

Uncertain

0.54

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.81

PhyloP100

2.1

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.40

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.016

Polyphen

1.0

Vest4

0.28

MutPred

0.34

Loss of disorder (P = 0.0092);

MVP

0.95

MPC

1.0

ClinPred

0.61

GERP RS

-0.57

PromoterAI

0.0023

Neutral

(source)

Varity_R

0.14

gMVP

0.25

Mutation Taster

=76/24

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over