2-118843217-C-G

Variant names:

• chr2-118843217-C-G
• NM_001426.4:c.900G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001426.4(EN1):​c.900G>C​(p.Glu300Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EN1 NM_001426.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.672
• Publications: 0 publications found

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]

EN1 Gene-Disease associations (from GenCC):

• ENDOVE syndrome, limb-only type

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13243514).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001426.4. 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
	EN1	NM_001426.4	MANE Select	c.900G>C	p.Glu300Asp	missense	Exon 2 of 2	NP_001417.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EN1	ENST00000295206.7	TSL:2 MANE Select	c.900G>C	p.Glu300Asp	missense	Exon 2 of 2	ENSP00000295206.5	Q05925
	EN1	ENST00000546667.1	TSL:5	n.*18G>C		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.67
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.24
Sift	Benign	0.14	T
Sift4G	Benign	0.50	T
Polyphen		0.016	B
Vest4		0.074
MutPred		0.21		Loss of methylation at K297 (P = 0.0839)
MVP		0.67
ClinPred		0.20	T
GERP RS		3.8
Varity_R		0.20
gMVP		0.58
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

hg19: chr2-119600793;