rs3824067

Variant names:

• chr7-155461246-T-A
• rs3824067
• NM_001427.4:c.686-1125T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001427.4(EN2):​c.686-1125T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.137 in 152,236 control chromosomes in the GnomAD database, including 1,553 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.14 (1553 hom., cov: 33)
• Consequence: EN2 NM_001427.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0270
• Publications: 3 publications found

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]

EN2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EN2	NM_001427.4	c.686-1125T>A		intron_variant	Intron 1 of 1	ENST00000297375.4	NP_001418.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EN2	ENST00000297375.4	c.686-1125T>A		intron_variant	Intron 1 of 1	1	NM_001427.4	ENSP00000297375.4

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20861 AN: 152118 Hom.: 1552 Cov.: 33

Gnomad AFR AF: 0.0649

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.194

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.153

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.152

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.137 AC: 20858 AN: 152236 Hom.: 1553 Cov.: 33 AF XY: 0.137 AC XY: 10193 AN XY: 74428

African (AFR) AF: 0.0647 AC: 2688 AN: 41550

American (AMR) AF: 0.147 AC: 2253 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.189 AC: 657 AN: 3472

East Asian (EAS) AF: 0.194 AC: 1005 AN: 5168

South Asian (SAS) AF: 0.112 AC: 539 AN: 4824

European-Finnish (FIN) AF: 0.153 AC: 1627 AN: 10608

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11611 AN: 68000

Other (OTH) AF: 0.151 AC: 319 AN: 2114

Alfa AF: 0.152 Hom.: 229

Bravo AF: 0.135

Asia WGS AF: 0.133 AC: 461 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.57
PhyloP100		-0.027
Mutation Taster		=100/0	polymorphism (auto)

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: rs3824067; hg19: chr7-155253941;