Genetic Variant EN1:p.Ala216_Ala217insAlaAlaValAlaAlaAlaAlaAlaAlaAla (chr2-118846520-T-TGCGGCCGCCGCCGCCGCCGCCACTGCCGCC) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_001426.4(EN1):c.618_647dupGGCGGCAGTGGCGGCGGCGGCGGCGGCCGC(p.Ala216_Ala217insAlaAlaValAlaAlaAlaAlaAlaAlaAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000671 in 148,966 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000061 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EN1
NM_001426.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.14

Publications

0 publications found

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]

EN1 Gene-Disease associations (from GenCC):

ENDOVE syndrome, limb-only type
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

EN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM4

Nonframeshift variant in NON repetitive region in NM_001426.4.

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.618_647dupGGCGGCAGTGGCGGCGGCGGCGGCGGCCGC	p.Ala216_Ala217insAlaAlaValAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 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.618_647dupGGCGGCAGTGGCGGCGGCGGCGGCGGCCGC	p.Ala216_Ala217insAlaAlaValAlaAlaAlaAlaAlaAlaAla	disruptive_inframe_insertion	Exon 1 of 2	ENSP00000295206.5	Q05925

Frequencies

GnomAD3 genomes

AF:

0.00000672

AC:

AN:

148858

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000150

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00000614

AC:

AN:

1139832

Hom.:

Cov.:

AF XY:

0.0000109

AC XY:

AN XY:

549034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23812

American (AMR)

AF:

0.00

AC:

AN:

12854

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17804

East Asian (EAS)

AF:

0.00

AC:

AN:

26378

South Asian (SAS)

AF:

0.00

AC:

AN:

32492

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3502

European-Non Finnish (NFE)

AF:

0.00000739

AC:

AN:

947298

Other (OTH)

AF:

0.00

AC:

AN:

45382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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

AF:

0.00000671

AC:

AN:

148966

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72644

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41220

American (AMR)

AF:

0.00

AC:

AN:

14982

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3410

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

66678

Other (OTH)

AF:

0.00

AC:

AN:

2064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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2-118846520-TGCGGCCGCCGCCGCCGCCGCCACTGCCGCC-TGCGGCCGCCGCCGCCGCCGCCACTGCCGCCGCGGCCGCCGCCGCCGCCGCCACTGCCGCC

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over