7-155458510-C-T

Position:

• chr7-155458510-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.07

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]

ACMG classification

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
EN2	NM_001427.4	c.133C>T	p.Arg45Trp	missense_variant	1/2	ENST00000297375.4	NP_001418.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EN2	ENST00000297375.4	c.133C>T	p.Arg45Trp	missense_variant	1/2	1	NM_001427.4	ENSP00000297375.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000255 AC: 3 AN: 1177350 Hom.: 0 Cov.: 30 AF XY: 0.00000176 AC XY: 1 AN XY: 569056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000369

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000103

Gnomad4 OTH exome AF: 0.0000211

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 27, 2023

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	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.81	L
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.28
MutPred		0.34		Loss of disorder (P = 0.0092);
MVP		0.95
MPC		1.0
ClinPred		0.61	D
GERP RS		-0.57
Varity_R		0.14
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-155251205;