chr2-118842949-C-A

Variant names:

• chr2-118842949-C-A
• rs200716631
• NM_001426.4:c.1168G>T

Variant summary

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

The NM_001426.4(EN1):​c.1168G>T​(p.Glu390*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000207 in 1,449,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EN1 NM_001426.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.47
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1168G>T	p.Glu390*	stop_gained	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.1168G>T	p.Glu390*	stop_gained	Exon 2 of 2	ENSP00000295206.5	Q05925

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449506 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 718168

African (AFR) AF: 0.0000301 AC: 1 AN: 33192

American (AMR) AF: 0.00 AC: 0 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26008

East Asian (EAS) AF: 0.00 AC: 0 AN: 39318

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53120

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102040

Other (OTH) AF: 0.00 AC: 0 AN: 59644

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.5
Vest4		0.72
GERP RS		5.1
Mutation Taster		=22/178	disease causing

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

dbSNP: rs200716631; hg19: chr2-119600525;