Genetic Variant EN1:p.Ala206_Ala213del (chr2-118846529-CGCCGCCGCCGCCACTGCCGCCGCG-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001426.4(EN1):c.615_638delCGCGGCGGCAGTGGCGGCGGCGGC(p.Ala206_Ala213del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,219,408 control chromosomes in the GnomAD database, including 35 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.0080 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00077 ( 26 hom. )

Consequence

EN1
NM_001426.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.33

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001426.4

BP6

Variant 2-118846529-CGCCGCCGCCGCCACTGCCGCCGCG-C is Benign according to our data. Variant chr2-118846529-CGCCGCCGCCGCCACTGCCGCCGCG-C is described in ClinVar as [Likely_benign]. Clinvar id is 3050668.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00796 (1179/148122) while in subpopulation AFR AF= 0.0263 (1080/40992). AF 95% confidence interval is 0.025. There are 9 homozygotes in gnomad4. There are 553 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EN1	NM_001426.4 link	c.615_638delCGCGGCGGCAGTGGCGGCGGCGGC	p.Ala206_Ala213del	disruptive_inframe_deletion	Exon 1 of 2	ENST00000295206.7	NP_001417.3	Q05925

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EN1	ENST00000295206.7 link	c.615_638delCGCGGCGGCAGTGGCGGCGGCGGC	p.Ala206_Ala213del	disruptive_inframe_deletion	Exon 1 of 2	2	NM_001426.4	ENSP00000295206.5		Q05925

Frequencies

GnomAD3 genomes

AF:

0.00798

AC:

1181

AN:

148014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00469

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.000166

Gnomad OTH

AF:

0.00737

GnomAD3 exomes

AF:

0.000480

AC:

AN:

18764

Hom.:

AF XY:

0.000253

AC XY:

AN XY:

11856

show subpopulations

Gnomad AFR exome

AF:

0.0260

Gnomad AMR exome

AF:

0.00236

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00185

GnomAD4 exome

AF:

0.000774

AC:

829

AN:

1071286

Hom.:

AF XY:

0.000688

AC XY:

352

AN XY:

511834

show subpopulations

Gnomad4 AFR exome

AF:

0.0277

Gnomad4 AMR exome

AF:

0.00273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000127

Gnomad4 SAS exome

AF:

0.0000853

Gnomad4 FIN exome

AF:

0.0000814

Gnomad4 NFE exome

AF:

0.0000956

Gnomad4 OTH exome

AF:

0.00236

GnomAD4 genome

AF:

0.00796

AC:

1179

AN:

148122

Hom.:

Cov.:

AF XY:

0.00766

AC XY:

553

AN XY:

72206

show subpopulations

Gnomad4 AFR

AF:

0.0263

Gnomad4 AMR

AF:

0.00468

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000166

Gnomad4 OTH

AF:

0.00730

Alfa

AF:

0.00577

Hom.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

EN1-related disorder

Benign:1

Jan 10, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over