rs2361689

Variant names:

• chr7-155462637-T-C
• rs2361689
• NM_001427.4:c.952T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001427.4(EN2):​c.952T>C​(p.Leu318Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,608,388 control chromosomes in the GnomAD database, including 92,113 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10156 hom., cov: 33)
  • Exomes 𝑓: 0.33 (81957 hom.)
• Consequence: EN2 NM_001427.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.92
• Publications: 15 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 7-155462637-T-C is Benign according to our data. Variant chr7-155462637-T-C is described in ClinVar as Benign. ClinVar VariationId is 1260669.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.92 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EN2	NM_001427.4	c.952T>C	p.Leu318Leu	synonymous_variant	Exon 2 of 2	ENST00000297375.4	NP_001418.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EN2	ENST00000297375.4	c.952T>C	p.Leu318Leu	synonymous_variant	Exon 2 of 2	1	NM_001427.4	ENSP00000297375.4

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54708 AN: 151950 Hom.: 10135 Cov.: 33

Gnomad AFR AF: 0.427

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.421

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.224

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.294

Gnomad MID AF: 0.327

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.366

GnomAD2 exomes AF: 0.362 AC: 85893 AN: 237086 AF XY: 0.362

Gnomad AFR exome AF: 0.432

Gnomad AMR exome AF: 0.496

Gnomad ASJ exome AF: 0.373

Gnomad EAS exome AF: 0.220

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.321

Gnomad OTH exome AF: 0.361

GnomAD4 exome AF: 0.332 AC: 482957 AN: 1456320 Hom.: 81957 Cov.: 51 AF XY: 0.335 AC XY: 242339 AN XY: 724062

African (AFR) AF: 0.433 AC: 14470 AN: 33396

American (AMR) AF: 0.486 AC: 21195 AN: 43602

Ashkenazi Jewish (ASJ) AF: 0.375 AC: 9772 AN: 26052

East Asian (EAS) AF: 0.242 AC: 9538 AN: 39458

South Asian (SAS) AF: 0.441 AC: 37860 AN: 85798

European-Finnish (FIN) AF: 0.305 AC: 16136 AN: 52918

Middle Eastern (MID) AF: 0.360 AC: 2073 AN: 5762

European-Non Finnish (NFE) AF: 0.317 AC: 351309 AN: 1109134

Other (OTH) AF: 0.342 AC: 20604 AN: 60200

GnomAD4 genome AF: 0.360 AC: 54762 AN: 152068 Hom.: 10156 Cov.: 33 AF XY: 0.361 AC XY: 26849 AN XY: 74316

African (AFR) AF: 0.428 AC: 17732 AN: 41468

American (AMR) AF: 0.422 AC: 6453 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1308 AN: 3466

East Asian (EAS) AF: 0.224 AC: 1155 AN: 5160

South Asian (SAS) AF: 0.429 AC: 2069 AN: 4822

European-Finnish (FIN) AF: 0.294 AC: 3111 AN: 10570

Middle Eastern (MID) AF: 0.328 AC: 95 AN: 290

European-Non Finnish (NFE) AF: 0.322 AC: 21894 AN: 67978

Other (OTH) AF: 0.362 AC: 763 AN: 2106

Alfa AF: 0.336 Hom.: 8490

Bravo AF: 0.371

Asia WGS AF: 0.329 AC: 1145 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	7.5
DANN	Benign	0.73
PhyloP100		2.9
Mutation Taster		=98/2	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: rs2361689; hg19: chr7-155255332; COSMIC: COSV52082670;